Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

• the invention is based, at least in part, on the discover)' that certain polymer films and particles can be utilized therapeutically and/or cosmetically.
• many of the films and particles described herein can. be ased for the controlled, localized, and sustained delivery of various agents for treatment of diseases and conditions.
• compounds and processes to prepare polymer based films, particles, gels, and related compositions, and processes for deliver)' of agents are provided herein.
• biodegradable polymers are also provided.
• the invention features oligomers or polymers having a repeat unit represented by Formula XX;
• Q is selected from among O, S, Se, or NH;
• G 555 selected from among fee following structures:
• R ⁇ is selected from among hydrogen, a straight or branched alky], cycloalkyK an.'!, olefin, siiyl, alkylsilyl, aryisilyl, alkyiaryl, arylaikyi, or tluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryi olefin, silyl, alkyisiiyl, arylsilyK alkyiaryl, aryiafkyl, or tluorocarbo ⁇ chain is optio ⁇ a ⁇ y substituted internally or terminally by one or more hydroxyl, hy ⁇ roxyetlier, oarboxyl, carboxyester, carboxyarnide,.
• Rj is selected from among hydrogen, roethoxy, etlioxy, amino, a straight or branched ⁇ lkyl, cycfoalkyl, aryl, olefin, siiyl ; alkyisiiyl, aryisilyl, alkyiaryl, or arylaikyi chain of 1-10 carbons;
• R ⁇ , Rs, and R ⁇ are each independently selected from among a straight or branched alky!, cycloalkyl, ary ⁇ , olefin, siiyl alkylsijyl, arylsilyl, aikylaryh or arylalkyl chain of 1 ⁇ I0 carbons; and R-?
• Rg are each .independently selected from among hydrogen, a straight or branched alky L cycloalkyi, aryl, olefin, aSkyl&ryl, or ary ⁇ alkyi chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, alkylaryL or arylalkyl chain is optionally substituted internally or terminally by one or more hydroxy 1, hydr ⁇ xyether, carboxyl, carboxyester, carboxyamide, ami.no, mono- or di-suhstiiute ⁇ amino, thiol, thioester, sulfate, phosphate, phosph.onate, or halogen subsiitueins,
• the oligomers or polymers are represented by Formula XX':
• n is an integer from 2-750, and each oligomeric or polymeric chain has a terminal group, the terminal goup being selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
• the invention features oligomers or polymers, or portions thereof, that are represented by Formula XXL XXlI, XXOI, XXIV 1 XXV ?
• Q' is independently selected from among O, S, Se, or NH;
• G 1' , G t ', avid G ⁇ ' are each independently selected from among the following structures:
• R is selected from among a straight or branched alky!, cydoalkyt aiyL, olefin, si!yl, alkylsily!, arylsilyi.aikylaryL arylalkyl, or fluorocarho ⁇ chain of 3-50 carbons, wherein each alky], cydoalkyl, aryl, olefin., silyt alkylsily!, arylsiiyl , alkylaryi arylalkyl or Ouorocarbon chain is optionally substituted internally or terminally by one or more hydroxy!
• Rj' is selected from among po!y(etby!ene glycol), po!y(elhylene oxide), poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an ammo acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a.
• R-. ' is selected from among a photocrosslinkab ⁇ K or ionicaliy cross ⁇ fikable group
• Ri' is selected from among hydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsiiyl, alkylaryl arylalkyl, or fluorocarbon chain of 1 -50 carbons.
• cyeloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl aikylaryl, arylalkyl, or Ouorocarbon chain is optionally substituted internally or terminally by one or more hydroxy!, hydroxyether, earboxyl, cai-boxyester, carboxyamide, amino, mono- or di-substituied amino, thiol, thioester.
• x and y axe each independently selected from an integer of 2-750; a is selected from an integer of 1-25; b is selected from an integer of I- 14; c is selected from an integer of 1-14; and each, polymeric terminal group is selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, metals, alkanes, alkenes and alkyncs.
• the invention features oligomers or polymers, or portions thereof, represented bv Formula XXXVIIf:
• Q' is independently selected from among O, S, Se, or NH;
• G f is selected from among or Rj';
• R 1 ' is selected from among a straight or branched alky), cyeloalkyl, aryl, olefin., silyl, alkylsiiyl, arylsilyl ⁇ lkylaryl arylalkys, or fluorocarbon chain of 3-50 carbons, wherein each alkyt eycloaikyl, aryl.
• olefin, silyl, alkylsilyl, aryis ⁇ yl, alkylaryl, aryialkyi or tiuorocarbo ⁇ chain is optionally substituted internally or terminally by one or more hydroxy], hydroxyetlier s carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substitiients: or R; : ⁇ s selected from among poiy(ethyiene glycol), poly(ethy!enc oxide), po!y(hydroxyacid)), a carbohydrate., a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or HKA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for
• oligomers or polymers G includes a first group that is convertible to a second group different from the first group at a pH at or below about 6.0, such as below about 5.5, 5,0 or 4.5;
• R z is selected torn among hydrogen, a straight or branched alkyl. cycloalkyl aryi, olefin, silyl, alkyls ⁇ yl, arylsilyl, alkylaryl arylaikyl, or i ⁇ uorocarbot) chain of 1-50 earboas.
• Each aikyl, cycloalkyl aryi, olefin, silyl, alkylsilyi, aryisilyl, alkylaryl, arylalkyl or fluorocarbon chain is optionally substituted internally or terminally by one or more hydroxy! hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-suhstivuted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen subatstuents: and Q is selected from among O, S, Se, or NH.
• the invention features particles having a first volume and .including an oligomer or polymer having a repeat unit represented by Formula XX;
• CJ includes a first group that is convertible to a second group different from the first group at a pH at or below about 6,0, such as below about 5.5, 5.0, or 4.5;
• R-. is selected from among hydrogen, a straight or branched alkyl. cycl ⁇ aikyl, aryi, olefin, silyl, alkylsiiyi, arylsilyl, a ⁇ ky ⁇ aryl, arylalkyl, or iluorocarbon chain of i-SO carbons.
• Each alky!, cyeloalkyi, aryS, olefin, silyl alkylsilyi, aryisi!yl ; alkylaiyl, arylalkyl, or tluoroc&vb ⁇ dvdn Is optionally substituted internally or terminally by one or more hydroxy], hydroxyether, carboxyl, carboxyester, carboxyar ⁇ ide, amino, mono- or di- substituted ammo, thiol, thioester, sulfate, phosphate, phosphomrte.
• the particle When the particle is placed in an environment having a pH at or below about 6.0, the particle increases in volume from the -first volume to a second volume that is more than two times the first volume after equilibrium is established.
• Polymeric films or particles can include any oligomer or polymer described herein, in some instances, the polymeric particles include a first volume at a first pil ami a second -volume at a second pH, different from the from the first pli.
• the second volume is IX or more greater than the first volume when the second pH is lower than the first v ⁇ U such as 4X or more greater than the first volume when the second pH is lower than the first pH, or SX or more greater than the first volume when the second pH is lower than the first pH,
• any Him or particle can include a therapeutic agent.
• the agent can be a biologically active agent comprising one or more of an anti-cancer agent, an anti- hiotic, an anti-neoplastic agent, an analgesic, an angiogenic, or an agent that promotes wound healing.
• the particles can be used fur applying to one or more of the following: (i) a surgical resection margin, (ii) within a treated or untreated tumor or cavity, (iii) a target site of disease away from a surgical margin, and (iv) a lymph node.
• the particles or films can have one or more layers.
• the particles can have a diameter or less than 500 nanometers, such as less than. 250 nanometers or less than 100 nanometers.
• the particles can have a diameter of between about 1 nm and 2 microns.
• any of the particles described herein can be applied at a first site, such as a surgical margin, and then are carried by She body to a second site downstream of the first site, such as a lymph node.
• Jt is desirable that the particles have a diameter of less than about 250 nanometers, such as less than !00 nanometers, or even less than 50 nanometers.
• the invention features applying any film or particle described herein Io treat pain, or to alter healing, e.g., to avoid scar formation.
• treating encompass either or both responsive laid prophylaxis measures, e.g., designed to inhibit, slow or delay the onset of a symptom of a disease or disorder, achieve a full or partial reduction of a symptom or disease state, and/or to alleviate, ameliorate, lessen, or cure a disease or disorder and/or its symptoms.
• amelioration of the symptoms of a particular disorder fay administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing oi " progression, or shortening of duration, whether permanent or temporary, lasting or transient thai can be attributed to or associated with administration of the compound or composition.
• subject is a human or an animal typically a mammal such as a cow, horse, dog, eat, pig, sheep, monkey, or other laboratory or domesticated animal.
• the term "patient” includes human and animal subjects,
• carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
• DMSO dimethyl sulfoxide
• pharmaceutical composition refers to a d ⁇ r ⁇ cal compound or composition capable of inducing a desired therapeutic effect, in a subject.
• a pharmaceutical composition contains an active agent, which is the agent that induces the desired therapeutic effect.
• the pharmaceutical composition can contain a prodrug of the compounds provided herein.
• a pharmaceutical composition contains inactive ingredients, such as, for example, carriers and exciplents.
• the term 'therapeutically effective amount refers to an amouru of a pharmaceutical composition sufficient to achieve a desired therapeutic effect.
• pharmaceutically acceptable refers to a fbrniuiation of a ccHTi pound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the fonm ⁇ ate ⁇ compound is administered to a subject.
• a pharmaceutically acceptable formulation does not cause significant irritation to a subject.
• pharmaceutically acceptable derivatives of a compound include, but axe not limited to, salts, esters, cnol ethers, eno ⁇ esters, ac ⁇ tals, ketals, orihoeste ⁇ s, hemiacerais, hemiketals, acids, bases, solvates, hydrates, PEGyiatioa, or prodrugs thereof.
• Such derivatives cars be readily prepared by those of skill in this art using known methods for such derivatization.
• the compounds produced can be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
• Pharmaceutically acceptable salts include, but are not limited to, amine sails, sucb as but not limited to chjor ⁇ proeaine, choline, N ⁇ '-diber ⁇ yl-eihyienediamine, ammonia, dieihanoi amine and other hydroxyalkylarnines, ethylenediamine, N- m ⁇ Jhylglucaminc, procaine, N-benzyl-phenethylamins, l-para-chloro-benxyl-2 ⁇ pyrroiidm- I '-ylr ⁇ ethyi-benzi ⁇ iidazoie, diethylamine and other alkylamines, piperazine and tiis ⁇ hydroxy ⁇ nethyi)-aminomethanc; alkali metal sails, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited Io barium, calcium and magnesium; transition metal salts, such, as but not limited to zinc; and
• esters include, bat are not limited to, alkyl, aikenyl . aikynyl. aryl., heteroaryi, araikyi. heteroaralkyi , cycloaikyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinie acids, sulfonic acids, sulilme acids and boronic acids.
• r ⁇ ol esters include, but are not limited to, derivatives of formula OC(QC(O)R) where R is hydrogen, alkyl, aikenyl, aikynyl, aryl, heteroaryi aralkyl heteroaralkyi, cycioaikyl, or heterocye ⁇ yL
• R is hydrogen, alkyl, aikenyl, aikynyl, aryl, heteroaryi aralkyl heteroaralkyi, cycioaikyl, or heterocye ⁇ yL
• Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or I to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent or water molecules.
• Alkyl refers to an aliphatic hydrocarbon group which can be straight or branched having 1 to about 60 carbon atoms in the chain, and which preferably have about 6 to about 50 carbons in the chain.
• Lower alkyl refers to mi alkyl group having I to about 8 carbon atoms.
• Higher alkyl refers to an alkyl group having about I Q to about 20 carbon atoms.
• alkyl group can be optionally substituted with one or more alkyl group substituents which can be the same or different, where "alkyl group substituem” includes halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkyithio, srylihio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo and cycioaikyl. There can " be optionally inserted along the alkyl chain one or more oxygen, silicon, sulfur, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is lower alkyl.
• Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
• exemplary alky! groups include methyl, ethyl. i-propyL n-butyl, t-butyl, a-pentyl, heptyl octyi, cSecyl, dodecyi, trl ⁇ eeyl, tetradecyl, pentadecyl and hexadecyl.
• Useful alkyl groups include branched or straight chain alky I groups of 6 to 50 carbon, and also include the lower alkyl groups of 1 to about 4 carbons and the higher alkyl groups of about 12 to about 16 carbons.
• alkenyl refers to an alkyl group containing at least one carbon-carbon double bond.
• the aikenyl group can be optionally substituted with one or more "alkyl group substituents.”
• alkenyi groups include vinyl aliyl, rt-pentenyl, dec ⁇ nyl, dodeeenyl, .etradecadienyl, heptadec-8-eti-l-yl and heptadec-8J i-dien-i -yt
• AIkynyr refers to an aikyl group containing a carbon-carbon triple bond.
• the a j ky ⁇ yi group can. be optionally substituted with one or more "alkyl group substitue ⁇ ts.”
• Exemplary alkyrsyl groups include ethy ⁇ yi propargyt n-pentyuyl, deeyrsyl, and dodecyrsyl, useful alkynyl groups include the lower alkynyl groups.
• Cycloalky refers to a non-aromatic mono- or trmltieyclie ring system of about 4 to about 10 carbon atoms.
• the cycioalkyl group can be optionally partially unsaturated,
• the eyeioalkyl grcmp can be also optionally substituted with an aryl group substil ⁇ ent, oxo and/or aikylene.
• Representative monocyclic cycloalky 1 rings include cydopentyl, cyciohexyi, and cyelohcptyL
• Usetul muliicyclic cycloalkyi rings include sdamantyl, octahydro ⁇ aphtbyl, decalin, camphor, cannphane, and ⁇ oradamantyi.
• Aryl refers to an aromatic earboeyci ⁇ e radical containing about 6 to about IO carbon atoms.
• the aryl group can be optionally substituted with one or more aryl group substituents, which can be the same or different, where "aryl group substifee ⁇ t” includes alkyl, alkenyi, alkynyl, aryl, aralkyl, hydroxy, alkoxy; aralkoxy, earboxy, aroyl halo, nitro, trihalomethyl, cyano, alfcoxycarbonyl, aryloxycarbo ⁇ yl, araikoxycarhonyl acyloxy, acyiamino, aroyiamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, rylthio, alkyltliio, slkylene, and -NRR', where R and R' are each independently hydrogen,
• acyl refers Io an aikyl -CO— group, wherein alkyl is as previously described.
• exemplary acyl groups comprise alkyl of I to about 30 carbon atoms.
• exemplary acyl groups also include acetyl, propa ⁇ oyi, 2-methy ⁇ r ⁇ parioyl, butanoyl, and pah ⁇ itoyl.
• Aroyl means an aryl-CO- group, wherein ary! is as previously described.
• Exemplary aroyl groups include benzoyl and 1 - and 2-naphthoy!.
• Alkoxy' 1 refers Io an a!ky]-O-- group, wherein alkyl is as previously described.
• exemplary alkoxy groups include rneih ⁇ xy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and beptoxy.
• Aryloxy refers to an aryi-O— group, wherein the aryl group is as previously described.
• Exemplary aryl ⁇ xy groups include phenoxy and naphthoxy.
• Alkylthio refers to an alkyl-S— group, wherein alky! is as previously described.
• Exemplary alkylthio groups include ineUiylthio, ethylthio, i-propylthio, and heptylthi ⁇
• ''Arylthio refers to an aryi-S-- group, wherein the aryl group is as previously described.
• exemplary arylthio groups include phenylthio and naphthylthio.
• Aralkyl refers to an aryl-alkyl— group, wherein aryl and alky! are as previously described.
• Exemplary aralkyl groups include benzyl, phemietbyl, and naphthylmethy],
• Alkyloxy refers to an aralkyl-O-- group, wherein the aralkyl group is as previously described.
• An exemplary aralkyloxy group is benzyloxy
• Alkyl&io refers to an aralkyl-S— group, wherein the aralkyl gxo ⁇ p is as previously described.
• An exemplary aralkyithio group is be ⁇ zyithio.
• Diaikykrmno refers to an -NRR' group, wherein each of R and R ( is independently an alkyl group as previously described.
• exemplary aikylamino groups include ethyhnethylamlno, dimetliylamino, aad diethylamiso.
• Alkoxycarbonyl refers to mx aiky1-O ⁇ -CO- group.
• exemplary aikoxycarbonyl groups include methoxycarbonyl, eihoxycarbonyl, butyioxycafbonyt, and t- buiyioxycarbo ⁇ yi.
• Aryloxycarbony refers to an aryl-O-CO-- group.
• Bxempiary aryioxycarbonyl groups include ph ⁇ rtoxy- and naphthoxy-cai'bonyl.
• Alkoxycarbonyl refers to an atalkyl-O— CO— group.
• An exemplary aralkoxycarbcniyl group is benzy ⁇ oxycarbonyi.
• Alkylcarbamoyl refers to a R 1 RN-CG- group, wherein one of R and R.' is hydrogen and the other of R and R' is alky! as previously described.
• Dialkylcarbamoy refers to R r RN-CO- ⁇ group, wherein each of R mid R' is independently alkyl as previously described.
• acyicrxy refers to an acyl-O- group, wherein acyi is as previously described
• acylamino refers to an acyl-NH— group, wherein acyi is as previously described,
• “Aroyiamhio” refers to an aroyl-NH— group, wherein aroyl is as previously described.
• “Aikyiene” refers to a straight or branched bivalent aliphatic hydrocarbon group having from ⁇ io about 30 carbon atoms.
• the alkylene group can be straight, branched. or cyclic.
• the alkyiene group can be also optionally unsaturated and/or substituted with one or more ' alkyl group substit ⁇ e ⁇ ts.” There can be optionally inserted along the alkyiene group one or more oxygen, sulphur, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen subsiituent is alkyl as previously described.
• Atkylene groups include methylene (--C ⁇ -h ⁇ ), ethylene (-CHrCH 2 -), propylene (-- (CHj) 3 ⁇ ), cydohexyicne (-C 6 Hj 0 --), -CH-CH -CfI-CH-, -CH-CH-CHr-, -- ⁇ C'F ?. )j) ⁇ Cib) tn ", wherein n is an integer from about 1 to about 50 and m is an imeger from 0 to about 50, -(CIb) n -N(R)-(CHj) 1 V 1 -, wherein each of m and ⁇ is independently an integer from 0 to about.
• SO and R is hydrogen or aikyL methylencdioxy (—0TM Cl-K-O-), and eihyi& ⁇ edfexy
• An alkyiene group can have about 2 to ahmn 3 carbon atoms and can further have 6-50 carbons.
• “HaIo'' or “halide” refers to fluoride, chloride, bromide, or iodide.
• agent includes without limitation, medicaments, vitamins, mineral supplements, substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness, substances that affect the structure or function of the body, or prodrugs, which become biologically active or .more active alter they have been placed irs a predetermined physiological environment.
• a “bioactive agent” refers to an agent that is capable of exerting a biological effect in vitro and/or in vivo, The biological effect can be therapeutic irs nature.
• bioacuv ⁇ agent refers also to a substance that is used in connection with an application that is diagnostic in nature, such as in methods for diagnosing the presence or absence of a disease m a patient.
• the bioactive agents can be neutral or positively or negatively charged.
• suitable bioactive agents include pharmaceuticals and drugs, cells, gases and gaseous precursors (e.g., O 2 ) .
• Genetic material refers generally to nucleotides and polynucleotides, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
• DNA deoxyribonucleic acid
• RNA ribonucleic acid
• the genetic material can be made by synthetic chemical methodology known to one of ordinary skill in the art, or by the use of recombinant technology, or by a combination of the two.
• the DNA and RNA can optionally comprise unnatural nucleotides and can be single or double stranded.
• Genetic material refers also to sense and anti-sense DNA and UNA, that is, a nucleotide sequence that is complementary to a specific sequence of nucleotides in DN. A and/or RNA.
• the polymers provided herein can be utilized therapeutically and/or cosmetically,
• the polymers in any form described herein can be used to promote healing and/or that inhibit disease by targeting drug delivery to local and regional areas.
• the polymers provided herein can also be used for a variety of applications including, but not limited to, production of micro- and nanoparticl.es, films, coatings, sutures, and orthopedic materials.
• Such materials can be used to repair an injured tissue, organ., bone, or genetic defect
• Other uses of the polymers provided herein include treatment of early, late, or previously treated malignancies, pretreatrnent of malignancies or other condition as a sensitizes' to augment therapy of another agent such as with radiation sensitizers, avoidance of iocoregional lymph node metastasis, augmentation of local wound healing and decrease m infection, manipulation, of structure and abnormal scar formation, and for the treatment of post-operative pain.
• the polymers provided herein axe used to treat cancer.
• the polymers provided herein can be used to treat various malignancies, e,g., lung, colon, prostate, pancreas, or breast cancer.
• a film carrying one or more therapeutic agents when utilized to treat a cancer, it can be stapled, sutured and/or glued in place, e.g., with a eyanoacryiate resin.
• the polymers provided herein can also be used to deliver any agent.
• the agent can be in any pharmaceutically acceptable form, including pharmaceutically acceptable sails, A large number of pharmaceutical agents are known in the ait and are amenable for use in the pharmaceutical compositions of fee polymeric materials described herein.
• Acceptable agents include, but are not limited to, chemotherapeutie agents, such as radiosensstizers, receptor inhibitors and agonists or other antineoplastic agents; immune modulators and bloaetive agents, such as cytokines, growth factors, or steroids with or without the co-incorporation of tumor or pathogen antigens to increase fee antineoplastic response as a means of vaccine development; local anesthetic agents; antibiotics; or nucleic acids as a means of local gene therapy.
• chemotherapeutie agents such as radiosensstizers, receptor inhibitors and agonists or other antineoplastic agents
• immune modulators and bloaetive agents such as cytokines, growth factors, or steroids with or without the co-incorporation of tumor or pathogen antigens to increase fee antineoplastic response as a means of vaccine development
• local anesthetic agents such as a means of vaccine development
• antibiotics such as a means of local gene therapy.
• Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of subjects.
• Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., dectroporation, lipo lection).
• Reactions and purification techniques can be performed, e.g., using kits according to manufacturer's specifications or as commonly accomplished in ihe an or as described herein.
• FlG. 1 is a bar graph showing the number of cells after treatment with 10- hydroxycampt ⁇ th ⁇ ciii loaded Sims, control films without lO-hydroxycamptothecin, blank films, and l ⁇ -hydroxycampiothecin alone.
• FIG. 2 is a bar graph showing the rmraher of cells after treatment with 10- hydroxycampiotheein loaded films, control films without 10-hydroxycam ⁇ tothecin, blank ilims, arsd IG-hydroxycamptotheein alone.
• FIG. 3 is a bar graph show-ing the cytotoxicity of po!y(g!yccro!-co-caprolactone ⁇ rsanopa ⁇ ides
• FRX 4 is a bar graph showing the cytotoxicity of p ⁇ iy(glycerol-co-caprohctone) iianopartidcs with 10% pac3iiaxei.
• FiCf 5 is a bar graph showing the cytotoxicity ofpoly(g!yccro]-co-capro]acione ⁇ na ⁇ >particks with 1 % p&clitaxeL
• FIG. 6 is a graph showing the release of 1 Q-hydroxyearapiothecin from polyOauric, myristic, pahn Uic. or stearic glycerol eatrbonate-co-caproiactone) films.
• F ⁇ G. ? is a graph showing 10-hydroxyca ⁇ iothecin release from polyCsiearic glycerol carbonate-co-caprolactone) films on pericardium strips.
• FlG. 9 is a graph showing particle swelling at various pHs.
• FlG, 1C) is a graph showing the deproteclioii observed by absorbance using IJV/Vis spectroscopy at a wavelength of 292 nm.
• FIG, 1 1 is a scanning electron microscope (SEM) image of ⁇ anoparticks.
• FICs. 12 is a graph of the diameter of sugar derived mmospheres at various pHs
• [ 1 ICs. 13 is a bar graph showing tumor volume in response to chemotherapy- loaded ⁇ anopariides.
• FiG. 14 is a bar graph showing tumor volume in response to subcutaneous polymer i ⁇ im implantation.
• FfG. 16 is a bar graph showing the anti-cancer activity of paclitaxei baded nanopartieles with LLC (king cancer) cells in vitro.
• FIG. 17 is a bar graph showing the activity of paciitax ⁇ l loaded iianoparticles with mesothelioma cells ia vitro,
• FIG. 13 is a bar graph showing the anti-cancer activity of pacliiax ⁇ l loaded na ⁇ partides with A459 human lung cancer cells in vitro.
• compositions for delivering agents.
• the following describes the synthesis of monomer units and the polymerisation of those monomer units. Also provided is the synthesis of polymeric structures that incorporate therapeutic agents and methods of using such compositions to treat various diseases and disorders.
• V in; v monomer units include compounds of Formula 1, II, and Ui: where each Q is independently selected from among O, S 5 Se, or NH; CL or G and Q together, are selected from among:
• R 5 is selected from among a straight or branched alky!, cycioalkyl, aryl, olefin, sih-1, alkylsilyL arylsilyl, alkylaryt aryMkyl, or fi ⁇ orocarbon chain of 3-50 carbons, wherein each alky L cycloalky], aryl, olefin, siiyl alky!si!yl 5 arylsilyl, alkylaryl, aryialkyi, or rluorocarbon chain is optionally substituted internally or terminally by one or more hydroxy), hydroxyeth ⁇ r, carboxyl, earboxyester, carboxyamide, amino, mono- or di- s ⁇ bstjtiued amino, thiol, tliioester, sulfate, phosphate, phosphonate, or halogen substitue ⁇ Us; ov
• R 5 is selected from among poiyCethylene glycol), poiy ⁇ ethylene oxide), poly(hydroxyacid) ⁇ , a carbohydrate, a protein, a polypeptide, aa amines acid, a nucleic acid, a nucleotide, a polynucleotide, any genetic material, such as a DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor; or
• Rj is selected from among a photocrossli ⁇ kabte or kmically crosslinkable group
• R comprises a first group that " is convertible to a second group different from the IJrst group at a pH at or below about 6.0;
• R-j is selected from among hydrogen, a straight or branched alkyl, cydoaLkyL ary ⁇ , olefin, silyi, aikyisilyl, arylsilyt alkylaryi aryialkyl or fluoroearbon chain of 1-50 carbons, wherein the alkyl, cycloaikyi, aryl, olefin, silyl, alk>-lsilyU arylsliyi, aikylaryi, arylalkyl or tluorocarfaoti chain is optionally substituted i ⁇ tenially or terrairsaliy by one or more hydroxy!, hydroxyether, carboxyl, carboxyesfer, carbo.xyaoiide> a ⁇ no, mono- or di -substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen
• the compound of Formula IH s a compound of Formula IV, where Q is oxygen.
• the compound of Formula ⁇ is a compound of Formula V, where Q is sulfur, hi certain embodiments.
• the compound of Formula Il is a compound of Formula VS, where Q is Se.
• the compound of Formula II is a compound of Formula VO, where Q is NFL
• a compound of Formula HI is selected from among a compound Formula VI!!, IX, X, or Xl, as shown above.
• the compound of Formula 111 is a compound of Formula VIIf where Q is oxygen, in certain embodiments, ihe compound of Formula II! is a compound of Formula IX, where Q is sulfur.
• the compound of Formula 111 is a compound of Formula X, where Q is Se.
• the compound of Formula III is a compound of Formula XI, where Q is NH,
• a compound of Formula II. is selected from among a compound Formula XlI, XiLI, or XIV, as shown below;
• the compound of Formula H is a compound of Formula XIL in certain embodiments, the compound of Formula Ii is a compound of Formula XML Irs certain embodiments, the compound of Formula II is a compound of Formula XlV.
• a compound of Formula Hi can also be independently selected from among a compound of Formula XY, XVI, or XVU, as shown above.
• each G group is selected from among a group shown videow:
• each Q is independently selected from among O, S, Sc, or Nil;
• R . is selected from among hydrogen, methoxy, ethoxy, amino, a straight or branched alkyh cydoaikyi, aryl, olefin, silyl, alkylsilvl, aryisiivL alkylar>1, or aryialkyl ⁇ chain of I - 10 carbons;
• R 4 and R 5 are each independently selected from among a straight or branched aJkyl, cycloalkyl, aryl, olefin, silyL alkylsilyl, aryisiiyl, alkylaryl, or arvlalkyl chain of 1 - ! O carbons; and
• R 7 is selected from among hydrogen, a straight or branched alky], 0 cydoaikyi, aryl, olefin, alky ⁇ aryl, or aryialkyl chain of 1-50 carbons, wherein the aikyi eydoalkyl, aryi, olefin, alkylaryl, or arylalkyl chain is optionally substituted internally or terminally by one or more hydroxy!, hyciroxyether.
• each G group is selected from among a group shown below:
• each G group is selected from among a group shown below:
• R ⁇ is selected from among a straight or branched aikyl cycioaikyl, aryl olefin, silyl, aikyls ⁇ y!, arylsiiyi, alkyhiryl, or aryl aikyl chain of 1-10 carbons; and
• Rg is selected from among hydrogen, a straight or branched aikyl, cycioaikyl, aryL olefin, alkykryl, or aryialky] chain of 1 -50 carbons, wherein the aikyl, cycioaikyl, aryl, olefin, alkykryi, ur aryklkyl chain is optionally substituted internally or terminally by one or more hydroxy!, bydroxyether,
• R ?. of Formula ⁇ is selected from among hydrogen, Cj-CV; alkyl. cycioaikyl, alkyjcycloalkyl, ary!, ajid heteroaryl.
• R 2 of Fomi ⁇ ia i is selected from among CrC 2 O alkyl, cydoaJkyl, ary L and heteroaryl.
• the R? of Fonmiia I is selected from among any group shown beSovv:
• R ⁇ of Formula ! is selected from among. t ' VC-ao alkyK C J -CJ O haloaiky), heteroaiky!, cycioalkyl, alkylcycioalkyl, aryi. and heteroaryi, wherein the alkyi, lialoalkyt hsier ⁇ aikyl, cycloalkyl, a ⁇ kylcycloalkyl, aryl, and beieroaryl axe optionally substituted, ⁇ n certain embodiments, Ih of Formula i is selected from among Cj-Cji!
• the R 2 of Formula I is selected from among any group shown below;
• lhe vinyl monomer units described herein can, e.g., be synthesized by reacting a compound of Formula I' to provide a compound of Formula I;
• HLG where each Q, G, or Q and G together, and R? are independently selected as defined herein; and LG is a leaving group such as Cl or Br.
• a compound of Formula .HQO where Q and G are as defined herein, is dissolved in a solvent such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, diohloromcthane, 1,4-dioxane, tetrahydrolunm (THF), acetone, acetonit ⁇ le (MeCN), di ⁇ ethylf ⁇ rr ⁇ ainide (DMF), diinethyl sulfoxide, acetic acid, n- butanol, isopropanol, ⁇ -propanol, ethanol, methanol or water.
• a solvent such as hexane, benzene, toluene, diethyl ether, chloroform
• a compound of Formula HQG is dissolved is THF. To this solution is added an acryloyl halidc, such as methaeryioyi chloride.
• a base such as a trialkyl amine (e.g. triethylamine) is added to the reaction mixture.
• the resulting product is a compound of Formula L in another embodiment, a compound of Formula ! is prepared by reacting a compound of Formula HQG, where Q and G are defined as above, with an aery! anhydride, such as mcthacrylic anhydride, in the presence of a base, such as triethy! amine.
• a compound of Formula I can be polymerized to yield a compound of Formula XX: where each Q, G 5 or G and Q together, and R 2 are independently selected as defined her « ⁇ >; and n is an integer from 2-750; and each polymeric terminal group is selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
• a compound of Formula 1 can be reacted with a free-radical initiator.
• Free-radical initiators include halogen molecules, such as Cl ⁇ , azo compounds, such as 2 1 2 > -azohis(2-methylpropu>nitri ⁇ e) (AIBN), and organic peroxides, such as di-t- butylperoxide.
• the polymerization can also be induced by light and a ph ⁇ toinitiator.
• a compound of Formula 1 is dissolved in a solvent, such as hexarse, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichlorome ⁇ ane. i.4- dioxaae, tetrahydrofura ⁇ (TlW), acetone, acetonitrile (MeCN). diniethylfbrmamide (DMF), or dimethyl sulfoxide, and reacted with AIBN to yield a compound of Formula XX.
• a solvent such as hexarse, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichlorome ⁇ ane. i.4- dioxaae, tetrahydrofura ⁇ (TlW), acetone, acetonitrile (MeCN). diniethylfbrmamide (DMF), or dimethyl
• the polymer of Formula XX is hydrophobic and contains a pH sensitive group.
• G groups that are pR sensitive can be selected from among the groups described herein.
• polymers of Formula XXi can be obtained by acid catalyzed hydrolysis from polymers of Formula XX, which contain a pH sensitive srouo.
• An v method of acid catalyzed hvdrolvsis known in the art can be used for this transformation.
• the hydrolysis can be realized by immersing the polymer of Formula XX into a hydrochloric acid solution.
• the pH of the solution can be between 0,1 and 6.5, In other embodiments, the p ⁇ ⁇ i of the solution is between 1 and 5,
• the pH can be bdow about 6.0, 5.5, 5,(1 4.5 or 4,0, IR certain embodiments, the pH around 4.
• the pi I sensitive group can be removed under basic conditions and/or can be cleaved enzymatically.
• the hydrophilic polymer of Formula XXI can increase in size as compared to the hydrophobic polymer of Formula XX.
• the increased size (S 5 ) can be between 1.5 and 20 or more times the original size (Si).
• the change m size from S f to Sj is between 2 and 20 times, e.g., between $ and IS 5 5 and 10, 2 and 4, or 8 and 10 times, the original size,
• a compound e.g., compound 1, 2, 3, 4, S, 6, 7, 8, 9, 10, 1.1, 1.2, 13, 14, 15, or 16.
• i.s polymerized alone or in combination with another monomer to form a polymer, e.g., compound Ia, 2a, 3a, 4a, 5a, 6a, 7a 5 Sa, 9a, 10a, J Ia, 12a, LIa, I4&, 15a, or 16a.
• Any method of polymerization described herein can be used for this transformation.
• a free-radical initiator such as 2,2' ⁇ azobis(2-methy3propionitrik ⁇ (AIBN).
• AIBN 2,2' ⁇ azobis(2-methy3propionitrik ⁇
• the resulting compound Ia, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a. 10a, ⁇ Ia, 12s, 13a, 14a, ISa 5 or 16a is generally a hydrophobic polymer with a pH sensitive group. Any method of ae ⁇ .1 catalyzed hydrolysis known in the art can be used to cleave the pH sensitive group, as described herein. Enzymatic hydrolysis alone, or in combination with an acidic or basic solution, can also be used to cleave the group.
• compound hi, 2a, 3a, 4a, Sa, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, or 16s can be immersed in a hydrochloric acid solution.
• the resulting compound Ib, 2b, 3b, 4b, Sb, 6fo, 9b, IiJb, lib, 12b, 13b, 14b, 15b, or 16b is a hydrophilic polymer and can increase in size between 1.5 and 20 or more times the original size of compound Ia, 2a, 3a, 4a, Ss, 6a, 7a, 8a, 9a, 10a, Ma, 12a, 13a, 14a, ISa, or 16a, respectively.
• compound- la, 2a, 3a. 4a, 5a, 6a, 7a, 8a, 9a, ⁇ Oa, .1Ia, 12a, 13a, 14a, 15a, or 16a can be exposed to an acidic solution for various periods of time. Longer periods of exposure can lead to greater swelling.
• Alternative methods of achieving gi eater growth include raising the temperature and lowering the pit. The degree to which the particle swells can be reduced by adding difuiictiona! crossiinkers.
• Difunetio ⁇ al crossliiikers include di-acryiaie species and provide crossiinking between ployiner chains that further restrict the size of the particle upon expansion.
• Compounds 5 and 6 are individually polymerized to form a polymer, e.g., compound Sa and 6a, as shown below; where each Q, n, R ⁇ . , R 4 , Rs, and temiinal group are independently selected as defined herein.
• Compound 7 and 8 arc individually polymerized to form a polymer, e.g., eoTupound Iz and Sa, as shown below:
• Compounds 13 aixi 14 are isidividualiv polymerized to fb ⁇ a polymer, e.g., compound !3a m ⁇ f4a, as shown below:
• €ompoimils 15 and 16 are individually polymerized to form a polymer, e.g., compound 15a and 16a, as shown below:
• any compound of Formula I can be co-polymerized with any vinyl monomer described herein or known in the art.
• Compound I cm be co-polymerked with Compound 2
• Compound 3 CM be co -polymerized with any vinyl monomer known m the ait, for example .methyl methaerylate.
• any compounds of Formula I can be co-polymerized with any vinyl monomer described herein or kn ⁇ vvn in the art to produce a random copolymer, a block copolymer, alternating copolymer, or a graft copolymer using any methods known in the art.
• any compound of Formula I can be co-poiwicrized with any vinyl monomer described herein or known in the art to yield a linear, branched, star, or comb polymer, again, using any methods known in me art.
• Any ratio of a single monomer relative to another monomer can be used to form a copolymer.
• Different ratios of monomer units impart different physical and ehermoai properties to the copolymer. Properties of interest include, but are not limited to, thermal transition temperature, bulk strength, crystaliiniiy, flexibility, elasticity, and hydrophobicity.
• properties of interest include, but are not limited to, thermal transition temperature, bulk strength, crystaliiniiy, flexibility, elasticity, and hydrophobicity.
• introduction of a bulky hydrophobic side group will make the polymer more hydrophobic and reduce the rate of hydrolysis, o
• polyesters poiyethers, polyether-esters, polyamides, polycarbonates, mid polyamino acids
• These polymers can be used to make the films, particles, gels, and related compositions 0 described herein, and can be used, e.g., to deliver various agents, e.g., bioacti ve agents,
• each Q ! is independently selected from among O, S, Se, or NH;
• G', G 5 ', and G 2 are each independently selected from among:
• R is selected from among a straight or branched aikyi cycbalkyl, aryl, olefin, si j yl, alkylsilylj aryisilyl, aikyJaryi, aryl alkyl or fluorocarbon chain of 3-50 carbons, wherein the alkyl. eyd ⁇ alkyi aryl, olefin, siiyl, aikyisifyl, aryi siiyl, alkyiaryi arylalky!
• ihiorocarhon chain is optionally substituted internally or terminally by one or more hydroxy!, hydroxyether, carboxyl.
• Rj' is selected from among poly(ethyiene glycol), poSy( ethylene oxide), poiy ⁇ hydroxyacid)). a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or a «y epitope for a biological receptor; or
• Rf ' is selected from among a photocrosslinkable or ionically cross! inkablc group
• R; ' comprises a first group that is convertible to a second group different from the first group at a p ⁇ -l at or below about 6.0;
• R->' is selected irons among hydrogen, a straight or branched alky!, eyeloalkyl, aryl olefin, siiy!, alkylsiiyl arylsilyl, alkyiaryl, arylalky!, or fluorocarbon chain of 1-50 carbons, wherein the alkyl, cydoalkyi, aryl, olefin, silyl, alkyisilyl, aryl siiyl, alkyiaryl, arylalkylj or iluorocarbo ⁇ chain is optionally substituted i ⁇ temaily or temii ⁇ ally by one or more hydroxy], hydroxyether, carboxyi, carboxyester, carboxyamide, amino, .mono- or di-substiti ⁇ ted amino, thiol, thioester, sulfate, phosphate, phosphorate, or halogen .substituents: x and y arc
• each Q ⁇ G', R 2 ', x, aid lei-iumai group are independently selected as defined herein: and a is selected from an integer of 1-25.
• each Q f . G', x, y. and te ⁇ ni ⁇ a ⁇ group are i ⁇ depeodently selected as defined; and b is selected from an integer of 1-14.
• compounds ⁇ f Formula XXXVI and XXXViI as shown below:
• each Q' ' , G 1 , x, y, and terminal group are independently selected as defined; and c is selected from an integer of 1-14.
• the C of Formula XXi-XXXVH is selected from among any group shown below;
• each R 1 '. G ⁇ G 2 ⁇ and G" group of any of Forni ⁇ la XXI- XXXVII is independently selected from among a group shown below:
• each Rj', Gi'.G?', and G' group of any of Formula XXf XXXVH is independently selected from among a group shown below:
• each RV 5 V- Ga', and G' group of any of Forrnuia XXI- XXXVO b mdepsindeiitly selected from among a group as shown below:
• each Q- is independently selected from among CX S, Se, or NH.
• each R;', G 5 ', G 2 ', and G' group of any of Formula XXI- XXXVIl is independently selected from among a group as shown below:
• each Q' is independently selected from among O, S, Se, or NH.
• XXXVO is independently selected from among a group as SIIOWB below;
• each Q' is independently selected from among O, S, Se, or NIL
• each R 5 ', Gj', G 2 ', and Cr group of any of Formula XX! XXXVIi is independently selected from among a group as shown below;
• each Q' is h ⁇ ]epcr ⁇ ien ⁇ ly selected from among (X S, Se, or NH.
• each R s ⁇ G ; ', G;> r ; and G' group of any of Fo ⁇ iiuia XX! XTXXVfI is independently selected from among a group aa shown below:
• the compounds of Formula XXXVIIl can be a random copolymer, a block copolymer, alternating copolymer, or a graft copolymer.
• the compound of Formula XXXVlO is a compound of Formula XXXIX, as shown below:
• the compound of Formula XXXYOI is selected from among a compound of Formula XL, XLl, XLIL or XLIIL as shown below;
• a compound of Formula XXXVIII is selected from among a compound of Formula XL where Q' is oxygen.
• a compound of Formula XXXYIO is selected from among a compound of Formula XLI where Q f is sulfur.
• a compound of Formula XXXVf H Is seseeicd irom among a compound of Formula X LH, where Q' is Se, in certain embodiments, a compound of Formula XXXVIO is selected from among a compound of Formula XlJIL where Q' is NH.
• the compound of Formula XXXVlII is selected from among a compound of. Formula XLlV, XLV, or XLVI, as shown below;
• a compound of Formula XXXViIi is selected from among a compound of Formula XLiV, in certain embodiments, a compound of Formula 5 XXXV ⁇ is selected from among a compound of Formula XLV. In certain embodiments, a compound of Formula XXXVlIl. is selected from among a compound of Formula XLVI.
• polymers of Formulas XX can be - XLVi.
• polymers of Formulas XXi-XL V] can be prepared by step- reaction polymerization, ring-opening polymerization, or by chain-reaction adduion polymerization.
• a polymer of Formula XXXVIII can be prepared by ring-c ⁇ e ⁇ img polymerization of a lactone monomer and a carbonate monomer.
• I Fs product of this reaction is a polymer of Formula XXXVHI where Q 1 is O, and C is benzyl where x, ⁇ e, and terminal group are independently selected as defined herein.
• any method of ring opening polymerization can be used for this reaction.
• the ring opening polymerization may be induced by healing ili ⁇ reaction, in one embodiment, the reaction is catalyzed by a metal catalyst, such as Sn(OCi) 2 .
• the reaction can be performed neat, or in the presence of a solvent, such as toluene, dichloromeihanc, or diethyl ether.
• Any ratio of monomers can be used, for example, the ratio of carbonate ixionoraer to lactone .ncnomer can be I : i , 1:2, i :3, 1 :4, 1 :S, 1 :6, 1 :7 S 1 ; S, 1 -9, or 1: 19,
• the lactone cars be a four, five, six, or seven membereii ring:
• Compound 17 is prepared by polymerizing a benxyloxy glycerol carbonate with oxeta ⁇ -2-onc;.
• Compound IH is prepared by polymerizing a bcnzyloxy glycerol carbonate with dihydrofuran-2(3H)-one.
• Compound 19 is prepared by polymerizing a benzyloxy glycerol carbonate with ⁇ eirahydro-2] f-py ⁇ ari-2-one.
• Compound 20 is prepared by polymerizing a benzyloxy glycerol carbonate with oxepan- 2-o ⁇ ie.
• Polymers of Formulas XXI-XLVI, wherein G' is a protecting group can be further modified to contain various side chains and pendant groups.
• G' can be any protecting group known in the art,
• G ! is a benzyl ether or benzylide ⁇ e protecting group.
• a polymer of Formulas XXi - XLV ⁇ cm be modified to contain a side group selected from among a straight or branched alkyi, cycloalkyL aryl, olefin, siiyl, aikyls ⁇ yl, aryLsilyJ, aikylaryl, arylaikyl or iluorocarbon chain of 3-50 carbons, wherein the aikyl, cycioalkyi aryt olefin, siiyl, aikylsily ⁇ , arylsilyl, alky ⁇ aryl, arylaikyl or fluoroearbon cMm is optionally substituted infernally or terminally by one or more hydroxy!, hydfoxyetbcr, earboxy
• sick chain groups can be seSccied from among p ⁇ iy(ethyiene glycol), poly ⁇ ethylene oxide ⁇ , ⁇ oly(hydroxyacid), a carbohytiraie, a protein, a polypeptide, an amino acid, a nuckic acid, a nucleotide, a polynucleotide, anv DKA or RNA seu ⁇ e ⁇ l a lipid, a polysaccharide, am antibody, a pharmaceutical agent, or any epitope for a biological receptor.
• a functional side chain can be incorporated into a. polymer of any one of Formulas ' KXI-XLVl, such as a photocrossimkabk or ionicafly cross!
• the benzyl ether can be cleaved to afford a hydroxy! group. Any method of cleaving a benzyl ether known in the art can be used for this transformation. For example, the benzyl ether can be cleaved by catalytic hydrogenation. The resulting hydroxy! group can be reacted with reactaiits or reagents to produce the polymer of Formula XXXVI! I with a non- hydrogen G' group. Any method of reacting an alcohol known in the art ca ⁇ i be used for this transformation .
• the polymer of Formula XXXV1 ⁇ I containing a hydroxy! mui ⁇ ry ears be moduli ⁇ l to yield a polymer with various G' groups.
• the alcohol can be reacted with a carboxyHc acid, such as stearic acid, oleic acid, or my ⁇ stk acid, In other embodiments, the alcohol is reacted with 6-bcnzyloxy-hexanoic acid, hexancciioic acid morsohenzyi ester, or imoc-6-amino-hexan ⁇ ie acid.
• the G' group is a carbonate, an ester, or an ether.
• x, y, e, and the terniinal group are independently selected as defined herein; and g is selected from an integer of 1-25.
• a polymer containing a hydroxy! moiety can be modified to produce a polymer with various groups.
• the alcohol can he reacted with a carbo ⁇ yhc acid, such as stearic acid, oleic acid, or mytistic acid, in other embodiments, the alcohol is reacted with a bcnzyloxy-aikyl acid, a aikyl acid monohe ⁇ xyl ester, or a protected animo-aJkyi acid.
• the benzyloxy, m ⁇ nobenzy], and fhioe protecting groups can be removed by methods known in the art to produce at! alcohol, a carboxylic acid, or a ⁇ amine, respectively.
• films ami particles can be formal tium polymers ofFo ⁇ nuias XX-XLVI. As shown below, various types of films and particles, such as micro- or nanoparticks, can be made itom polynicrs of Formula XX and XXXVf II. Any of the polymeric lilms and panicles described herein can be made to incorporate bio&ctive, e.g.. therapeutic, agents within the polymer structure to produce a polyrner/agent complex. Any method known in ihe art can be used to form a polymer/agent complex from, the monomers and p ⁇ iyrners dcscribc ⁇ l herein.
• each Q 1 Q : , G, G', t% R 2 , x, y, e, and terminal group are independently selected as de&ied herein.
• the polymers described herein can be used to produce fihns using techniques known in the art.
• a polymer of Formula XX or XXXVlII is dissolved in an organic solvent, e.g., dichloromethane, tetmhydrofura ⁇ , toluene, or an aqueous solution and deposited onto a solid surface, such as a glass surface.
• an organic solvent e.g., dichloromethane, tetmhydrofura ⁇ , toluene, or an aqueous solution
• the polymer is dissolved in a solvent along with an agent, sach as i 0- hydroxyeamptotl'secisi, and deposited onto a solid surface, such as a glass surface.
• the solvent is then allowed io evaporate to afford a polymeric film either at ambient temperature or pressure, or at elevated or reduced temperatures aud/or pressures.
• the polymer solution is deposited onto the solid surface using a syringe, e.g., a microsyringe.
• the polymer solution is deposited onto the solid sorlace, e.g., glass, mica, polymer, collagen, pericardium, TEFLONCik metal, metal alloy, ceramic or an oxide, using a spraying device, such as an aerosol device.
• films containing a polymer of Formula XX or XXXVIII can be formed by dissolving the polymer in an organic or aqueous solution, or a mixture of organic and aqueous solutions, and applying the solution to a surface.
• films containing a polymer of Formula XX or XXXVlH are formed by melting the polymer, ' The melted polymer can be applied to a solid surface, such as glass.
• the polymer is applied to & solid surface and is then melted to form a polymeric film, in certain embodiments, multi-layered films are prepared. For exan ⁇ k% a polymer is deposited onto a solid surface as described above to produce a film.
• each polymer film is produced from a polymer of Formula XX or XXXV 111
• 1 , 2, or 3 of the layers include a polymer of Formula XX or XXXVHL and either !
• 2, or 3 other layers include a different polymer, such as polytiactic acid), poiyigiycohc acid), poly ⁇ iac-ie ⁇ eo-glycofic acid), polycaprolactonc, poly(triraeth!ene carbonate), polyester, polycarbonate, or polyamide.
• the various layers or fillers can be selected to dissolve orbiodegrade at different rates to produce devices in which different agents are included in different layers and are released at different rates.
• a first agent can be included in a first surface layer designed to provide a rapid release, e.g., within a few hours or days
• a second agent CM be included in a second layer designed to provide an extended release profile, e.g., 1 week, 2, 3, 4, 5 weeks, or even more.
• an other surface layer can be designed not to release any agent, but to m early delay release of agents in subsequent layers.
• a patterned polymer filrn is prepared by using a microprinter or a micro-syringe.
• a microprinter or microsyringe can be used to deposit a solution containing a polymer of Formula XX or XXXVlH onto a solid surface, such as a glass surface.
• the microprinter or mkrosyringe deposits die solution in a controlled marmer to form patterns s ⁇ ch as stripes and/or dots, ' flic solvent is removed by evaporation. This method ears be performed with more than one polymer simultaneously.
• a solution containing a polymer of Formula XX or XXXVlO and an agent such as 10 ⁇ hydroxyeamptothecin, may he deposited onto a solid surface by this technique t ⁇ a fiord a patterned agent containing film.
• Such patterned films can deliver agents to specific biological areas and tissues, aa determined by the specific pattern of agent loaded within a film.
• the polymers described herein can be used to product; micro- or nanopartides using methods known m the art.
• a water in oil emulsion technique is described by Edkmd and co-workers (see Edlund at aL, Adv. Polymer SeL 157:67-1 12, 2001 ; arsd Wang ei aL, Chem, Fharm. Bull,, (Tokyo) 44:1935, 1996).
• a polymer is dissolved in dichioromethane using a vortexing device. !. ⁇ certain embodiments, the polymer is dissolved in dicbJorornethane along with an agent, such as paclitaxei.
• the solution is placed in a 5% polyvinyl alcohol surfactant and vortexed (or sonicated using a probe tip sonicator) and stirred for 16 hours to produce micropartides.
• the niieropar ⁇ cles are collected and washed with distender ⁇ /deionked water and lyophilized.
• To produce isasioparticles one can for example, use a minienmlsicn polymerization method (see, e.g., Landfester et a!. n Maeromoleeules. 32:5222-8, 1999).
• a monomer as described herein and a free-radical initiator such as Ch, 2,2 ; - azobis ⁇ 2-mclhyfpropionitriie) (AIBN), or di-t-b ⁇ tylperoxidc
• a solvent such as hexane, be ⁇ zene, toluene, diethyl ctlier, chloroiomi, ethyl acetate, dieWoroniethaiie, 1,4-dioxane, tctr&liydrollsran (THF), acetone, acetonitriie (MeC'N), dimeihyifo ⁇ naiiiide (DMF), or dimethyl sulfoxide.
• a solvent such as hexane, be ⁇ zene, toluene, diethyl ctlier, chloroiomi, ethyl acetate, dieWoroniethaiie, 1,
• an agent sudu as paclitaxei is also dissolved in the solvent.
• the solvent is removed via rotary evaporation uiUif a viscous mixture remains.
• the viscous mixture is mixed with a stabilizing surfactant, such as a solution of sodium dodecyl sulfate, m a buffer solution. This mixture is sonicated for 1 hour (I second pulses with a 2 second delay) ⁇ ih 30 W of power, which forms die mimemuision and allows the solvent to evaporate.
• the mimemulsi ⁇ n is transferred into a temperature-controlled oil bath and stirred at 65 0 C for 2 hours to initiate the free-radical polymerization.
• the resulting polymeric smoospheres are dialyzed. e.g., against 5 raM pH 8 phosphate buffer, acdate buffer, bicarbonate buffer, or sodium citrate butler, e.g., over two days, to remove excess surfactant and salts.
• nanoparticles can be produced by pbotoinitiation.
• a monomer as described herein can be dissolved in a solvent, such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, diehloromcthan ⁇ , 1 ,4-di ⁇ xane, tetrahydroiuran (THF), acetone, aeeiorritrite (MeCN), dimethylforrnam.de (DMF), or dimethyl sulfoxide.
• a solvent such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, diehloromcthan ⁇ , 1 ,4-di ⁇ xane, tetrahydroiuran (THF), acetone, aeeiorritrite (MeCN), dimethylforrnam.de (DMF), or dimethyl sulfoxide.
• an agent such as paelitaxe
• the viscous mixture is mixed with a stabilizing surfactant solution, such as sodium dodecyl sulfate, in a buffer solution.
• a stabilizing surfactant solution such as sodium dodecyl sulfate
• the mixture is then sonicated for 30 minutes ( 1 second pulses with a 2 second delay) with 30 W of power, forming the roiniernulsion and allowing the solvent to partially evaporate.
• Eosirs Y and I-vinyl-2- pyrrolidone are added to the emulsion.
• the mixture is then exposed to light from a source such a.s a mercury arc lamp while the solution is stirred vigorously.
• the resulting particles are stirred overnight while open to the air to allow any remaining solvent to evaporate.
• the polymeric nanopartieles are then di&lyzed against a buffer solution to remove excess surfactant and salts.
• Polymeric particles can also be prepared by a precipitation method.
• a polymer of Formula XXXVIII is dissolved in a solvent, such as dichSoro ⁇ ietha ⁇ e, along with an agent, such, as pacliiaxel.
• the solution is added to an aqueuous surfactant solution, such as sodium dodecyi sulfate in water.
• the resulting mixture is sonicated to produce an emulsion.
• the mixture is stirred while open to ihe atmosphere to evaporate the excess solvent, such as dichoromethane.
• the resulting particles are collected and optionally ⁇ iaiyzed using a membrane with a molecular weight cutoff to remove excess surfactant.
• the diameter of the particles formed is between t ⁇ tn and SO microns, e.g., between. LO ran and 1 micron, between SO rssi and I micron., between 100 nm and 500 nm, or between 1 and 50 microns.
• Encapsulation ⁇ of an. Ageist Within. Polymeric Particles Any method known in the art for encapsulating an agent within a polymeric particle can be used to form a polymer/agent complex. For example, an oil emulsion technique is used to form paclitaxe! containing particles of Formula XX.
• a polymer of Formula XX can be dissolved in a solvent, such, as diehloromethane, in the presence of an agent, such as paelitaxet
• the polymer/paclitaxei solution is vortexed.
• a surfactant solution such as 5% polyvinyl alcohol, is added to the p ⁇ iymer/paditaxel solution, and the resulting solution is vortexed for about 15 minutes followed by stirring for about KS hours.
• the encapsulation efficiency of paelitaxei by the particles using ibis technique is between 30-99%.
• the encapsulation efficiency of paclitaxc! by the particles using tnis technique is between 60-75%.
• a polymer film or particle described herein can incorporate a pharmaceutical agent selected from among (1 ⁇ nonsteroidal anti-inflammatory drags (NSAIDs) analgesics, such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, lenta ⁇ yl, hydromorphone.
• NSAIDs nonsteroidal anti-inflammatory drags
• analgesics such as diclofenac, ibuprofen, ketoprofen, and naproxen
• opiate agonist analgesics such as codeine, lenta ⁇ yl, hydromorphone.
• salicylate analgesics such as aspirin (ASA) (enteric coated ASA);
• Hi -blocker antihistamines such as clemastine and terfenadme;
• Ha - blocker antihistamines such as cimetidirte, famotidine, iiizadine, and ranitidine;
• anti-infective agents such as mupirocin;
• C 7 ⁇ antianaerobic auti-infectivcs such as chloramphenicol and clindamycin;
• ⁇ 8 ⁇ antifungal antibiotic ami-infeetives such as amphotericin b, clotrimazole, fluconazole, and ketoeonazole;
• macrolide antibiotic anti-infectives such as azithromycin and erythromycin; ⁇ 10) miscellaneous beta-lactarn antibiotic arsti-hyfeciives, such as azireonam and i
• a ⁇ ti -infectives such as isoniazki (LNH), and rifampin;
• antiprotozoal anti-infcctives such as aiovaqiionc and dapsone;
• antimalarial antiprotozoal ami -infectives such as chloroquine and pyrimethamine;
• ami -retroviral anti-infectives such as ritonavir and zidovudine;
• antiviral anti-infective agents such as acyclovir, ganciclovir, interferon alpha, and rimantadine;
• alkylating antineoplastic agents such as carbop Latin and cisplati ⁇ ;
• nitrosourea alkylating antineoplastic agents such as ca ⁇ nusti ⁇ c (BCNU);
• antimetabolite antineoplastic agents such as methotrexate
• (5-FU) and geradiabine (23) hormonal antineoplastics, such as gosereli ⁇ , leupmlkk. and tamoxifen; (24) natural antineoplastics, such as aldesleukin, interleukin-2.
• antibiotic natural antineoplastics such as bleomycin, dactinomycin, ⁇ au ⁇ orubiein, doxorubicin, and mitomycin
• vioca alkaloid natural antineoplastics such as vinblastine and vincristine
• autonomic agents such as nicotine
• anticholinergic autonomic agents such as benztropine and trihexyphenidyl
• antimuscari ⁇ ie anticholinergic autonomic agents such as atropine and oxybuiynin
• ergot, alkaloid autonomic agents such as bromocriptine
• (31) cholinergic agonist parasympathomimetics such as pilocarpine
• choli nest erase uih.ibi.tor parasympathomimetics such as
• blocker antianginals such as nifedipine and verapamil
• nitrate antianginals such as isoxorbide dinitrate (ISDN)
• cardiac glycoside antiarrhythmics such as digoxin
• class I anti-arrbsthmics such as lid ⁇ eame, niex.ilct.inc, phenytoin, procainamide, and qui ⁇ i ⁇ e
• class Il antiarrhythmics such as atenolol m ⁇ toprolol, propranolol and timolol
• class III antiarrhythmics such as amiodarorsc
• class IV antiarrhythmics such as diltiazem and verapamil
• alpha-blocker antihypertensives such as prazosin
• angiotensin- converting enxyme inhibitor (ACE inhibitor) antihypertensives such as capt.
• agents such as colchicine, isotretinoin, methotrexate, minoxidil; tretinoin (ATRA);
• dermatologieai corticosteroid anti-inflammatory agents such as betamethasone and dexamethasorse:
• betamethasone and dexamethasorse antifungal topical aaii infectives, such as amphotericin B, clotrimazole, .miconazole, and nystatin
• antiviral topical arHi-in.feet.ives antiviral topical arHi-in.feet.ives.
• acyclovir such as acyclovir; (62) topical antineoplastics, such as il ⁇ oro uracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosemidc; (65) potassium-sparing diuretics, such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents, such, as probenecid; (68) enzymes such as RNase and DNase; (69) immunosiipr «ssive agents, such as cyclosporine, steroids, methotrexate tacrolimus, sirolimus, rapamyein; (70) antiemetics, such as prochlorperazine; (71) salicylate gastrointestinal anti-inflammatory agents, such as sulfasalazine; (72) gastric acid-pump inhibitor anti-ulcer agents, such as omeprazole;
• benzodiazepine anticonvulsants such as clonazepam, diazepam, and lonrzcpara
• anti-parkisonian agents such as bromocriptine, levod ⁇ pa, carbkiopa, and pefgol ide
• KMV anti-vertigo agents, such as meclizine
• opiate agonists such as codeine, fentanyl, hydromorphone, methadone, and morphine
• opiate antagonists such as naloxone
• beta-blocker anti-glaucoma agents such as timolol
• (1 10 ⁇ miotic anti-glaucoma agents such as pilocarpine
• ophthalmic aminoglycoside antimfcetivcs such as gentamicin, neomycin, and tobramycins
• (1 12 ⁇ ophthalmic quinolone anii-infectives such as
• ophthalmic corticosteroid an ti- inflammatory agents, such as dexamethasone and prednisolone;
• ophthalmic nonsteroidal ami-inflammatory drugs such as diclofenac;
• antipsychotics such as clozapine, haioperidol, and risperidone;
• benzodiazepine anxiolytics, sedatives and hypnotics such as clonazepam, diazepam, ioraz.epara, oxazepam, and prazepam; ⁇ !
• ebJofhexIdme estradiol eypionate in oik estradiol valerate in oil
• flurbiprofen ilurbiprofcn sodium
• ivermectin ievodopa
• nafarelin nafarelin
• the following drugs can also be used: recombinant heta-gkcan; bovine immunoglobulin concentrate; bovine superoxide dismutase: the formulation comprising iiuoro ⁇ raeil, epinephrine, and bovine collagen; recombinant hirudin Cr-HIr) 5 HlV-I immunogen; human anti-TAC antibody, recombinant human growth hormone (r-hGH); recombinant human hemoglobin fr-Hb); recombinant human mecaserrain (r-fOF-1 ⁇ ; recombinant interferon beta- Ia; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan.
• recombinant heta-gkcan bovine immunoglobulin concentrate
• bovine superoxide dismutase the formulation comprising iiuoro ⁇ raeil, epine
• intraveru) ⁇ s products can be used; acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; earmustine; dactinoinyci ⁇ , daunorubkin HO; d( ⁇ ;etaxd; doxorubicin HCl; epoetin alpha; ctoposide (V'P-l ⁇ ); tluorouracil (S-FU); ganciclovir sodium: gentai ⁇ cin sulfate; interferon alpha; ieuprohde acetate; meperidine HCI; metliadone HCl; methotrexate sodium; paciitaxel; ranitidine HC); vinbiastm sulfate: and zidovudine (AZT).
• aldesleukin aldesleukin
• atenolol
• useful pharmaceutical agents from the above categories include: (a) antineoplastics such as androgen inhibitors, antimetabolites, cytotoxic agents, receptor inhibitors, and ⁇ nmunomodoktors; (b) anti-iussives such as dextromethorphan, dextromethorphan hydrobromide, noseapin ⁇ , carbetapenta ⁇ e citrate, and cMorphedia ⁇ oi hydrochloride; (c) antihistamines such as chlorpheniramine maleat ⁇ , phenindaminc tartrate, pyrilamine vnaleate, doxylaroine succinate, and phenyltoloxaniiae citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine
• Hydrochloride pseudoephedrine hydrochloride, and ephedrine;
• various alkaloids such as codeine phosphate, codeine sulfate and morphine;
• mineral supplements such as potassium chloride, zinc chloride, calcium carbonates, magnesium oxide, and other alkali metal and alkaline earth metal salts;
• ion exchange resins such as cholestyramine:, (h) anti-afrhythrnies such as N-acety! ⁇ rocainaniide;
• antipyretics and analgesics such as acetaminophen, aspirin ami ihuprofen;
• appetite suppressants such as phenylpropanolamine hydrochloride or caffeine;
• Ic expectorants such as guaifenesin;
• antacids such as aluminum hydroxide and magnesium hydroxide;
• biologicals such as peptides, polypeptides, proteins and amino acids, hormone
• TGF-beta fibroblast growth factor
• FGF fibroblast growth factor
• NNF- uipha & beta nerve growth factor
• GHRF growth hormone releasing factor
• epidermal growth factor (EGF) fibroblast growth factor homologous factor (FCiFMF)
• FCiFMF fibroblast growth factor homologous factor
• HGF hepatoeyte growth factor
• IGF insulin growth factor
• invasion inhibiting faet ⁇ r-2 CllF-2 bone rnorphogenetie proteins 1-?
• BMP 1--7 somatostatin, thymosin ⁇ alpha-K gar ⁇ ma-gi ⁇ bu ⁇ n, superoxide dismuta.se (SOD), complement factors, liGH, t.PA, ANF, EFO and insulin;
• anti-infective agents such as antifungals, anti- virals, antihekmnths, antiseptics and antibiotics;
• oxygen henioglobin, nitric or s ⁇ ver oxide.
• Non-limiting examples of broad categories of useful pharmaceutical agents include the following therapeutic categories: anabolic agents, anesthetic agents, antacids, anti-asthmatic agents, anticholesterolei ⁇ ic and ant j -lipid agents, anti-coagulants, anticonvulsants, imti-diarrheais, antiemetics, anti-infective agents, ami-inflammatory agents, anti-manic agents, anti-nauseanis, antineoplastic agents, anti-obesity agents, anii -pyretic and analgesic agents, anti -spasmodic agents, anti-thrombotic agents, an ⁇ -urkexr ⁇ e agents, anti-anginal agents, antihistamines, anti-tttssives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotic
• drugs examples include; asparaginase, bleomycin, busuli ' an, capecitahine, carboplati ⁇ , ca ⁇ nustine, chlorambucil, cispiaiin, cyclophosphamide, eytarabine, dacarbixine, dac ⁇ otnyci ⁇ , tfaunorubicin, dexrazoxane, docetaxd, doxorubicin, etoposide, iloxuridlne.
• fludarabine iluoruraoil, ger ⁇ citabi ⁇ e, hydroxyurea, idarubicin, ifosraraide, irinotecr ⁇ , lomustine, medilorethamme, raelphalan, mereapi ⁇ purme, methotrexate,, mitomycin, mitotane, mitoxantrone, paclit ⁇ d, pcntostatin.
• pLicamycm premextred procarbazine, muximabe, strcptozoci ⁇ , teiiiposid, tl ⁇ iogua ⁇ ime, thiotepa, vinpkstiae, vinehristine, and vinordbine.
• the currently preferred drugs for lung cancer treatment is paditaxel, pemeirexed, l()-tiydrt>camptothecin, iri ⁇ otecan, erlotinihtL ' gefetinsb or derivates of these molecules.
• caiTiptothecins examples include caiTiptothecins. These drugs are antineoplastic by virtue of their ability to inhibit, topoisomerase I.
• Cainpiothecin is a plant alkaloid isolated I ⁇ o.m trees indigenous to China and analogs thereof such as 9- a ⁇ n ⁇ cas ⁇ iothecm, 9-nitrocaBipiothecin, 10-hydroxycamptotbeein, 1OJ 1 - methylenedioxyca ⁇ iptothecin, 9- ⁇ itro ⁇ 10, 1 1 -jnethylenehydroxyeasnptothecin, 9-chloro- 10, 1 l-methylend ⁇ ydroxycaiTiptothecin, 9-amino- 10.1 1 -metbyienehydroxycampi ⁇ tii «ci ⁇ , 7-ethyl-l( ⁇ -hydroxyca « ⁇ ptothecift (SN-3S), lopotecan, DX-S9S I
• the pharmaceutical agent can he a radiosensitizer, such, as met ⁇ ciopramide, scnsainide or neiisensamide (manuiactured by Oxigene): profu-omyci ⁇ (made by Vion); R SR 13 (made by Ailos); THYM ⁇ TAQ ⁇ (made by Agouron), etmiidazole or lobenguane (manufactured by Nycor ⁇ cd); gadolinium texaphrin (made by Pha ⁇ nacyciics ⁇ ; BuDR/Broxine (.made by NeoPharm); IPdR (made by Spuria); CR2412 (made by Cell Therapeutic); LlX (made by Terrapin); agents that mimm ⁇ e hypoxia, and die like.
• a radiosensitizer such, as met ⁇ ciopramide, scnsainide or neiisensamide (manuiactured by Oxigene
• the agent can be selected from a biologically active substance.
• the biologically active substance can be selected from the group consisting of peptides, poly-pep tides, proteins, amino acids, polysaccharides, growth factors, hormones, a ⁇ ti-angiogenesis factors, interferons or cytokines, elements, and pro-drugs.
• the biologically active substance is a therapeutic drug or pro-drug, most preferably a drug selected from the group consisting of chemotherapeutic agents and other antineoplastics such as paclitaxel, antibiotics, anti-virals, antifungals, anesthetics, aniihelmi ⁇ ths, anti- inflammatories, and anticoagulants.
• the therapeutic drug or pro-drag is selected from the group consisting of chemotherapeutic agents and other antineoplastics such as paeliiaxel, carb ⁇ pla ⁇ and cisplatin; nitrosourea alkylating antineoplastic agents, such as eamiusiine (BCNU); ffuoroufseil (5-FIj) and gemeitahine; hormonal antineoplastics, such as gosere ⁇ n, lei ⁇ roiide, and tamoxifen; receptor inhibitors such as erioiinib, gefeii ⁇ ib, sutent or anti-cklt inhibitors, such as GLEBVEC&; natural antineoplastics, such as aldesleukin, interteukin-2, docelaxel, etoposide (VP- 16), interferon alpha, paclitaxel, and tretinoin (ATRA),
• chemotherapeutic agents and other antineoplastics such as paeli
• the biologically active substance is a nucleic acid sequence.
• the nucleic acid sequence can be selected from among any DNA or RNA sequence.
• the biologically active substance is & DNA sequence thai encodes a genetic marker selected from among iuciferase gene, ⁇ -gaUctosidase gene, .resistance, neomycin resistance, and chloramphenicol acetyl transferase,
• the biologically active substance is a DNA sequence that encodes a lectin, a rnannose receptor, a siaioadhesin, or a retroviral trans-activating factor.
• the biologically active substance is a DNA sequence thai encodes a RNA selected from the group consisting of a sense RNA, an antisense RNA, siRNA and a ribozyr ⁇ e.
• Biologically active agents amenable for use with the new polymers described herein include, without limitation, medicaments; vitamins; mineral supplements: substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
• Useful active agents amenable for use in the new compositions include growth factors, such as transforming growth factors (TGFs). fibroblast growth factors (FGFs) 3 platelet derived growth factors (PDGFs), epidermal growth factors (HGFs), connective tissue activated peptides (CTAPs) 5 osteogenic .factors. and biologically active analogs, fragments, and derivatives of such growth factors.
• TGFs transforming growth factors
• FGFs fibroblast growth factors
• PDGFs platelet derived growth factors
• HGFs epidermal growth factors
• CTAPs connective tissue activated peptides
• TGF transforming growth factor
• ITrF supergene family include the beta-transforniing growth factors (for example. TGF-M, TGF ⁇ b2, and TGF ⁇ b3); bone raorphogenetie proteins (for example, BMP-I, BMP-2, BMP-3 : BMP-4, BMP-S, BMF-6, BM.P-7, BW-S 5 and BMP-9); heparin-binding growth factors (lor example, fibroblast growth factor (FGF) 5 epidermal growth factor (EG F), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF)); mhlbins (for example. lnhibin A, lnhibin B); growth differentiating factors (for example, GDF- 1): and activins (for example, Activin A, Aetivin B, and AcHvin AB),
• the polymers provided herein can be utilized to promote healing or treat or inhibit disease by targeting daig delivery to local and regional areas.
• the polymers provided herein can also be used for a variety of applications including, but not limited to, production of micro- and aanopariicles, films, tissue scaffolding, coatings, sutures, and orthopedic materials.
• the polymers can also be used in various cosmetic applications, such as tissue augmentation. Such materials can be used to repair an injured tissue, organ, bone, or genetic defect.
• the polymers provided herein include treatment of early; late, or previously treated malignancies or to inhibit recurrence of cancers that have been, surgically removed or locally treated, avoidance of locoregional lymph node metastasis, augmentation of local wound healing and decrease in infection, manipulation of structure and abnormal scar formation, and for the treatment of postoperative pain.
• the polymers provided herein are used to treat cancer.
• the polymers provided herein can be used to treat king, colon, prostate, pancreas, or breast cancer. They could also be used with bone marrow transplantation to targsi residual tumor ceils in the graft, such as iympohomas and leukemias.
• the polymeric particles can be injected or infused into or around inoperable tumors to locally deliver drugs, such as chemotherapy or sensitizers, or injected or iri&sed near the site of the operation incision to deliver agents such as antibiotics, anesthetics, or growth or healing factors, thereby avoiding side effects associated with systemic delivery.
• the polymeric panicles provided herein can be administered at a site of surgery with the Intent of the particles being carried by the lymph fluid to loco-regional nodes.
• the ⁇ particles can become trapped at the lymph nodes, allowing delivery of agents to tumor cells that also commonly migrate to lymph nodes.
• Cells that commonly migrate to lymph nodes include tumor cells and immune cells such as T ceils or dendritic ceils, and thus direct presentation of antigen by the particles can be utilized to enhance the immune system.
• the particles can be used to treat tumors systemicalty either by targeting the tumor ceils directly or by upreguiatii ⁇ g the immune system to fight the tumor,
• the polymeric particles and films provided herein can also he administered to sites where tumor regrowtli is likely to occur.
• the particles and films can be administered to areas where, as a consequence of disease, such as COPD or inflammatory howl disease, or systemic chemotherapy, poor healing will result in major complications.
• the particles and films can be administered to the margins of a surgical excision or resection, or to sites following local ablative therapy, for such applications, the polymeric particles are prepared Io adhere to the surgical margin or be retained within the confines and perimeter of the mass,
• the particles or films adhere to the pericardium, cartilage, or collagen for the delivery of anti-cancer or antineoplastic agents,
• the films can be stapled, sutured, and/or glued in place at a site. hi other erab ⁇ dk ⁇ emtx.
• the films and particles described herein can be used in cosmetic applications. In such an application, the swelling associated with pH changes can be advantageously utilized.
• the acrylate polymers described herein upon delivery to a tissue site swell and increase in size and bulk, filling voids.
• Such polymers can he used without any agents to fill wrinkles or to increase the size of tissue, e.g., in the lips or checks.
• the polymers could deliver cosmetic agents such as BOTOX® and/or analgesics.
• the net result of such a treatment could be, e.g., a smoothing of facial tissue, in some embodiments, the polymers used for such an application are, e.g., 3a-6a and 9a and 10a. Any method of adhering particles to biological tissue can be used for this application.
• the polymeric particles provided herein can be coated with PluroTiie FI 27.
• the particles are entrapped within a gel, hydr ⁇ gef > adhesive, sealant or surgical reinforcement strip made from pericardium, TEFLON®, plastic, or other materials or particles that can utilize a specific bound such as biotin-avidirs to increase there resident time at the implant site.
• other types of surgery can benefit from the use of the polymeric particles and films described herein.
• films and particles that contain antibiotics can be utilized for local delivery at a surgical site. The release rate of the antibiotics ar ⁇ i/or analgesics can be prolonged to reduce the risk of post -surgical infection, such as Clostridium difficile infection.
• This method provides an alternative to the use and risk of systemic antibiotics, 'Hie films and particles can contain anesthetics, such as local amide anesthetics, IY narcotics, or anti-inflammatory agents, such as steroids or NSAlDS, to reduce the discomfort of patients.
• anesthetics such as local amide anesthetics, IY narcotics, or anti-inflammatory agents, such as steroids or NSAlDS
• the use of such polymeric materials can reduce morbidity secondary to delirium and constipation, decrease the length of hospital slays for patients, and reduce overall health care costs.
• the polymeric films and particles are in contact with aqueous or organic solutions, or combinations thereof.
• the aqueous solutions can be selected from among water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates or combinations of any two or more thereof.
• the organic solutions cars be selected from among DMSO, ethanoL, methanol, THF, dichloromethanc. DMF, hexane or toluene or combinations of any two or more thereof.
• the polymeric particles and films can contain genetic materials, e.g., nucleic acid sequences. Such materials can be used to tnmsfeet cells in vitro, ex vivo, or hi vivo.
• the polymeric particles and films can contain a receptor recognizing a targeting moiety, allowing specific entrance into a cell or activation or inhibition of a cell receptor or subsequent intracellular signaling or apopototic pathway.
• the polymeric materials described herein can be used to deliver nucleic acid sequences to a cell or to deliver agents that can be transported to the nucleus of a ceil or effect transcription or translation within a cell, such as steroids or specific transcription factors
• the methods of using the polymeric particles and films described herein can be used separately or they can be combined with one or more therapies to treat a single patient.
• particles containing one type of therapeutic agent car be designed and delivered m a manner that results in the particles becoming entrapped at lymph nodes, whereas other particles or films that contain either the same or a different therapeutic agent can be applied to surgical margins or suture sites.
• Ii should also be recognized that other agents besides chemotherapeatiu agents, e.g.. cytokines, growth factors, and antiinflammatory agents, can be used in these methods and combinations of particles containing a variety of cher ⁇ otherapeutie or other agents can be employed, to both kill tumor, foster healing, and decrease pain.
• the polymeric mieropariieles, nanopartieies, Sims, gels, and other polymer forms provided herein can be used for in vitro and in vivo manipulation of drug release kinetics. Depending upon the polymer selected, the rate of drug release can be delayed or immediate, In certain embodiments, the polymers provided herein can be used for prolonged drug delivery after an initial period of quiescence to permit surgicai healing to occur, in other embodiments, the polymeric panicles provided herein provide a dual mechanism of delivery where a daig is released from the particles and fee particles swell to destabilize or destroy the cell or cellular compartment ⁇ e.g., endosome).
• the particles cars swell and become lodged, embedded, or otherwise Immobilized at a certain target location due to the enlarged size of the particle.
• led particles can became lodged or embedded within a cavity, node, tubule, bronchus, or capillary and can be used to occlude blood flow as an embolization agent for bleeding, arteriovenous malformations, or tumor devasc ⁇ larization or can be used to prevent airflow to a specific portion of the lung as for endoscopic lung volume reduction surgery, to cite only two examples of potential uses of this property.
• Particle swelling can be triggered by pi!
• Such particles can also be manufactured to release agents that manipulate healing or fibrosis to facilitate permanent or temporary closure of the occluded lumen or cavity.
• Certain embodiments of the invention are directed towards polymeric films that are designed to deliver chemolherapeutic agents locally at surgical sites, with incorporation into the resection margin. These funis are used, e.g., In the treatment of cancer patients, where delivering drugs locally has the advantage of avoiding side effects associated with systemic drug delivery. These Elms allow the delivery of agents at local concentrations that could not otherwise be achieved due Jo drug toxicity.
• the films can release agents at the site of surgery and the released agents can dsf ⁇ se to areas of close 5 proximity to the implantation site and to the site of metastatic tumor growth.
• the implanted polymeric films am deliver one or more anti-cancer agents, e.g., as described herein, thai will act upon cancer or metastatic cells remaining at the surgical margins after luniur excision is performed. Urns, the films can reduce t ⁇ c incidence of tumor recurrence at a resection margin after remove] of cancerous tissue.
• the polymeric films can cover the chest wall to treat diseases such as mesothelioma or in other body cavities for diseases such as sarcomas.
• the polymeric films can incorporate local anesthetics or IV narcotics and be applied along an entire surgical incision for peri- operative analgesia, or incorporate
• Polymeric films containing a single or multiple agents can ho applied to a solid surface in a controlled manner to form patterns such as stripes and dots.
• Single or multiple agents can be incorporated in any pattern to achieve precise therapeutic delivery
• a further embodiment of the invention is the use of multi-layer films to alter the release of the agentCs).
• a film composed of a polyester-co-carbonate of 80:20 capr ⁇ ic acid and glycerol-stearic acid can be loaded with a drug, such as taxol, caroptoiheci ⁇ i, or
• the film can then be coated with another polymer of the same or different composition that does not contain the drug, form ing a multi-layered l ⁇ lm.
• the top po ⁇ yi ⁇ er layer which does not have the drug, acts as a sacrificial layer ihat first inhibits the release of the drug from the underlying film, hut as the top layer degrades, the bottom layer starts to release the drug. In this fashion, delayed and controlled release can occur
• Hie agent can be m any pharmaceutically acceptable form, including pharmaceutically acceptable salts.
• a large number of pharmaceutical agents are known in the art and arc amenable for use in the pharmaceutical compositions of the polymeric materials described herein, Acceptable agents are described elsewhere herein, and include, but are not limited to, ebemotlierapei ⁇ ie agents, such as radiosensitizers, receptor inhibitors and agonists or other antineoplastic agent; immune modulators and bioactive agents, such as cytokines, growth factors or steroids with or without the co-incorporation ⁇ f tumor or pathogen antigens to increase the antineoplastic response as a means of vaccine development; local anesthetic agents; antibiotics; or nucleic acids as a means of local geae therapy,
• the biologically active substances and agents are used in amounts that are therapeutically effective. While the effective amount of a biologically active substance will depend on the particular material being used, amounts of the biologically active substance from about 1% to about 65% can be desirable. Lesser amounts can be used to achieve efficacious levels of treatment for certain biologically active .substances.
• the amount of drug delivered per area of film or per particle will depend on the therapeutic range of the drug, its toxicity when delivered locally, and the clinical characteristics of fee patient being treated.
• the number of particles or amount of film delivered to a site is selected depending on factors such as 1) the amount of agent delivered per particle, 2 ⁇ the therapeutic range of the agent, 3) the local toxicity of the agent, and 4) the clinical characteristics of the patient being treated.
• the development of dosages based on these parameters is routinely performed by those skilled in the art of pharmacology and clinical medicine.
• the release kinetics of a given polymer film or particle can be fme-amed and adjusted by varying the ratio of monomer units and/or by modifying the .side chains of a given copolymer.
• a family of copolymers with varying release kinetics can. be used to accommodate the delivery of several different drugs with differing desired release kinetics. For example, making more side chains along the polymer that are hydrophilie will generally make the polymer more hydrophilk overall and will also generally increase the release rate of an agent from the polymer,
• the polymeric particles or films delay release of ehemotherapeutic agents.
• the delayed release can coincide with wound healing.
• drug delivery is delayed for a period of approximately 0-6 weeks.
• the drug is released over a period of 1-6 weeks,
• ⁇ m drug is released over a period of 2 weeks.
• the drug is released for «p to 3 months.
• One method of controlling the rate of release from the panicles is by varying the ratio of different monomer units during polymerization. For example, a ratio of 20:80 of glycerol and caproic acid provides polymers and resulting niicroparticles that release drug over live days.
• the size of the polymer particles described herein are between 2 arsd 100 nm in diameter, In other embodiments, the size of the polymer particles are between 0.02 - IC) micrometers in diameter, In other embodiments, the size of the polymer particles are between I -50 micrometers in diameter.
• Other polymeric particles of a larger size can be useful at specific sites, such as where tumor regr ⁇ wth is prevalent.
• polymeric particles of a larger size can be useful at a surgical margin, where suturing or stapling has occurred, or within a na ⁇ ve or treated tumor such as an ablated cavity secondary to radiofrequency ablation or other therapy, or within a spontaneous cavity such as occurs in squamous cell carcinoma. Placement of polymeric particles within other spontaneous cavities could be utilized to result in sclerosis of the cavity, cither with rclea.se of specific sclerosing agents such as tale powder, alcohol or d ⁇ xvcyeb ' n as examples or other inflammatory agents. This approach can then he utilized is the treatment of bullous disease in emphysema or infections diseases such as ecchmococeal cysts, tor example.
• the sew monomers and polymers can also be used to prepare biodegradable oligomers, polymers, maer ⁇ mokcuies, and copolymers using standard techniques.
• the oligomers, polymers, macromolecules and copolymers can contain alkyi side chains formed between [1 ] a monomer or snacromoiecular unit containing at least one functional side group; ⁇ 2 ⁇ alky! chains containing 1-50 carbon units; and, in certain embodiments. 13 J a structurally diftbresit monomer or macromolecular unit.
• the macrornolecular materials can be elastic solids or viscoelastic solids.
• the macror ⁇ oiecuiar materials provided herein are hydrophobic or hydrophilic.
• a macromolecular material provided herein undergoes a change from hydrophobic to hydrophilic in response to a change m pHL
• the macromolecular materials provided herein swell to a size that destabilizes or destroys a ceil or cellular compartment.
• the ScWenk flask was partially submerged in a thermostatted oil bath, preheated to 140 °C. Toluene (400 ⁇ L) was added to the catalyst and the mixture was injected via syringe to the monomers. The reaction was stirred for 48 hours, removed from beat, and cooled Io room temperature. The polymer was dissolved m didilorometbane (10 mb) ami precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation, The resulting polymer formed either a viscous oil or white solid precipitate depending on the carbonate content of the copolymer. Copolymers were formed with the following carbonate mole fractions: 0.05, 0.10, 0,20, 0.30, 0.40, 0.50, 1 .00.
• PolyChenzyloxy glycerol carbonate-co- ⁇ -capr ⁇ laclone ⁇ ( 1.0 g, 2.02 mmoi) was dissolved in 50 ml- dry dichlorometliane inside a Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OB ⁇ yC (50 mg ⁇ were then added to the solution.
• the reaction mixture was evacuated and purged with hydrogen three times. The flask was then pressurized to 60 psi with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Celite and the filter cake washed with 50 mL diehlororacthane. The solvents were then evaporated to yield the ii ⁇ al polymer.
• the resulting polymer formed either a viscous mi or white solid precipitate depe»dmg on the carbonate content of the copolymer.
• Copolymers were formed with the following carbonate mole fractions: 0.05, 0.10, 0,20, 0,30, 0.40, 0.50, 1.00.
• Table " I below indicates the composition, molecular weight and thermal data of the different copolymers, which are illustrated by structural formulas below the table, it Table I, CL : ⁇ eaprolactone; CG carbonate of glycerol f c ⁇ zzz mole percent carbonate monomer in polymerization feed; F cg ,- mole percent carbonate monomer in copolymer; M n - number average ⁇ rsoJeeuiar weight: FDl :::: polydixpersiiy index; T g ::: glass transition temperature; T 1 . ::: crystallization temperature; T !a ⁇ melting temperature . Hp- heat of fusion.
• Poiy(l>enzylox.y glycerol carbo ⁇ ate-co- ⁇ cap ⁇ olaeUme ⁇ i.O g, 2.02 mrnoi
• myristie acid 0.690 g, 3.03 mmol
• DMAP draeibylaminopyridhie
• DCC Dicyclohexyicarbodii ⁇ dc
• the precipitate* compound was isolated by filtration and the filtrate was concentrated.
• the concentrated filtrate was dissolved in diebioromeiba ⁇ e and precipitated in cold .methanol (25 nil..).
• the solvent was decanted and subsequently dried by evaporation.
• the resulting polymer was a white solid precipitate.
• Poiyfbe ⁇ zyloxy glycerol carbonatc-co ⁇ -caprofacto.ne (1.0 g, 2.02 mmol).
• stearic acid (0.859 g, 3,03 iranoi) and DMAP (0,123 g, 1.01. mmol) were dissolved in 1.00 mL dry diclilorometliane.
• !3CC (0.500 g, 2.42 rnmol
• Olcoyl chloride (183 mg, 0.65 mmol) was added drop by drop. The mixture was stirred for 24 hours at worn temperature under nitrogen. The pyridine was removed under vacuum, the crude product was dissolved in dichloromethane, and precipitated in cold methanol (25 rat). The solveM was decanted and subsequently dried by evaporation, The resulting polymer was a white solid precipitate.
• Fmoe-6-amino-hex.ano ⁇ c acid (11277 g, 0,78 rnol).
• poly(5-hydr ⁇ .y-I,3-dioxan-2- o ⁇ e-co- ⁇ -caprolaclo ⁇ e) ( 1.5 g, 2.6 ramol. 22 moi % carbonate), DCC (0.129 g, 0,63 mmol). and DMAP (0.032 g, 0.26 ramol) were dissolved in !3CM (20 mL). The solution was stirred at RT for 18 h. The DCXi was filtered and the solvent evaporated. The product was dissolved in dickiorometha ⁇ e (10 mL) and precipitated in cold methanol.
• the copolymer (300 mg) was dissolved in a 40 % mixture of piperldine (16 T ⁇ L) and dry dimethyl formamide (24 mL ⁇ and the reaction was stirred for 90 mm. The solvents were evaporated under reduced pressure. The product was dissolved in dkhi ⁇ r ⁇ ietha ⁇ e (IO mL) and precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation (quantitative yield). Complete deprotectio ⁇ was determined by ihe absence of the Fmoc protecting group peaks in the 1 H NMR spectrum at 4.88-4,95 (m, 211 CB 3 ), and 7.24-7.75 (m, 5 H, aromatic).
• a primary alcohol-derivitized copolymer poly(6-hydroxy-hexanoic acid 2-oxo- 13-dioxa ⁇ -5-yI ester-co-s-caprolactone) was synthesized using the following steps. Synthesis of 6-henzyhxy-hexanoic acid
• the copolymer (300 r ⁇ g) was dissolved in 50 mL dry dlcMororn ethane inside a Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OH) 2 /C (50 mg) were tliei ⁇ added Io the solution.
• the reaction mixture was evacuated and purged with hydrogen three times. The flask was then pressurized to 60 psl with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Cclit ⁇ and the filter cake washed with 50 mL ⁇ 3iehlorometlia&e. The solvents were then evaporated to yield the final polymer (quantitative yield). Complete deprotcction was determined by the absence ofthe benzyl protecting group peaks in the Hi NMR spectrum at 4.48-4.53 (s, 2H, PIiCH 3 ), 7.27-7.31 Cm, 5Ii, aromatic).
• a carboxyiic acid-derivhixed copolymer poly(hexanedioic acid mo ⁇ o- ⁇ 2-oxo-l,3- dioxan-5-y! ester- ⁇ o-K-caproIactorse ⁇ was synthesized using the following steps. Synthesis ofhexanedioic acid mofiobenryi ester
• F ⁇ iyfhaxaiiediok acid mono ⁇ 2-oxo- 1 ,3 ⁇ oxan ⁇ 5-yl) esler-co-c-caprolactone
• Hexanedioic acid monobenzyl ester (0.184 g, 0.78 mmol)
• polyCvhydi-oxy-U- dioxan-2-o.nc--co- ⁇ -caproIactone (1.5 g, 2.6 mnioL 22 mol % carbonate)
• DCC (0.129 g, 0.63 mmo ⁇
• mx ⁇ DMAP 0.032 g, 0,26 fnrnol were dissolved in dkhloromethane (20 ml.).
• the copolymer (300 mg) was dissolved in 50 mL dry dschloromethane inside a Pan bottle. 10% Pd/C (50 mg) and 20% Fd(OHVC (50 mg) were then added to the solution. The reaction mixture was evacuated and purged with hydrogen three limes. The Il ask was then pressurized to 60 psi with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Celite and the filter cake washed with 50 mL dichlorornethane. The solvents were then evaporated to yield the fmal polymer (quantitative yield). Complete deprotectioii was determined by the absence of the benzyl protecting group peaks m the ; !i NMR. spectrum at 5.06 (s, 2H, PhCTy, ?.2?-7.33 (m, 511 aromatic).
• Example 13 Polyfbenzyl ⁇ xy glycerol thiol carhonate-co-g-eaprolactorie
• Polyfbe ⁇ zyloxy glycerol thiol carbomtte-co- ⁇ -eaprolactone ⁇ is dissolved hi 50 mL dry dkhlor «nietbane inside a Parr bottle. 10% Pd/C (50 mg ⁇ and 20% Pd(OF! ⁇ 2 /C (50 mg) are added to the solution. Hie reaction mixture is evacuated and purged with hydrogen three times. The flask is pressurized to (SO psi with hydrogen and shaken for 24 hours. The reaction mixture is filtered through Celiie and the filter cake washed with 50 mL of diditoromethaue. The solvents are evaporated to yield the final polymer.
• Bioabsorbable poly DX-laetiik-eo-glyco ⁇ de (PLGA) mieroparticics can be used for the delivery of paclitaxcl.
• the fabrication techniques used to create PLGA microparticles were modified from Edluiid & Albertsson and Wang el. a!. (Edkmd et a.L, Adv. Polymer Sci, 1 57:67- I I 2, 2001 ; Wang ei aL, Cham. Fharm. Bull, (Tokyo) 44: 1935, 1996 ⁇ and utilized a water in oil emulsion technique.
• the solution was placed in 10 mi of 5% polyvinyl alcohol surfactant (Fisher) and vortexed for 15 minutes (or sonicated using a probe tip s ⁇ ieator ⁇ and stirred overnight.
• the mieropartieles were collected and washed three times in 30 ⁇ i L of distil led/deionized water. Following washing, the rmeropartieles were lyop ' bilize-d (ireexe dried) and stored at -2O 0 C to insure the stability of PaditaxeL
• the encapsulation efficiency of taxol by the microparlieles was determined to be 74% -f/- 4% by HPLC analysis.
• Example 17 Syndiesis of Na ⁇ oparticjcs by MiniemulsioR Nanoparricles were prepared using a modification of a miniemulsio ⁇ polymerization method previously reported (Landfester ei aL, Macrom ⁇ iecuies 32:5222- 8, 1999). Bdelly.
• This viscous oil was then mixed with a solution of sodium dodecyl sulfate, the stabilizing surfactant, in 20 mM triethanoiamme buffer. This mixture was then sonicated for 30 min (I s pulses with a 2 s delay) with 30 W of power, forming the raid emulsion and allowing the solvent to partially evaporate. Following somca ⁇ on, Eosin Y and I -vinyl-2-pyrrolidone were added to the emulsion Io give final concentrations of 0.2 rnM and 2 mM., respectively.
• This mixture was ⁇ hesi exposed to H giit from a mercury arc lamp operating at 300 W for 10 min while being stirred 'vigorously, causing polymerization. Following pholopolymerization, the particles were stirred overnight while open to the air to allow any remaining solvent to evaporate. ' The resulting polymeric nanopartieies were then diaiyzed against 5 mM pH S phosphate buffer over two days to remove excess surfactant and salts.
• Na.no ⁇ artides were prepared by first dissolving the polymer (50 mg) in Ci-i ⁇ Cb (1.0 ml) and dissolving sodium dodecyl sulfate (50 mg ⁇ in ⁇ eionized water (10 mL).
• ⁇ tanoparticles were prepared by first dissolving the polymer (50 mg) and paclitaxel (0,5 Big) ift CHaCb . (1.0 mL) and dissolving sodktin dodeoyl sulfate (50 nig) m ddomzed water (10 mL).
• Poly ⁇ hydroxy glycerol carbonale-co- ⁇ -eaprolacto ⁇ ie ⁇ mkrop&rtici ⁇ s were used for the delivery ofpemetrexed.
• the fabrication techniques used to create the r ⁇ icropartieks utilize a water in oi! in water emulsion technique.
• 0.5 g of 20:80 poly ⁇ hydroxy glycerol earbonate-co- ⁇ -caproJactone) was dissolved in 4 rnL diehtoromethane (Sigma Aldricli, St. Louis, MO) using a vortexing device. Alter the polymer was completely dissolved, 50 mg of pe ⁇ ietrexed previously solubilized m 0,9% NaCL was added ami further vortexed.
• the nanopartlcle stock solution (5 mg/ ⁇ iL) was diluted to a final concentration of 0.01 mg/mL with serum- free medium (Dulbecco's Modified Eagle Medium).
• serum-free medium Dulbecco's Modified Eagle Medium
• A549 human lung carcinoma ceils (American ' Type Culture Collection, Ma ⁇ assas. VA) were plated o.nk> a 96 well phis at a density of 5,000 cells/we!! and incubated overnight, or until about 90% confluence.
• the medium from each well was removed and replaced with 100 ⁇ i, oi ' O.QI mg/mL nanoparticle solution and the cells were subsequently incubated with the particles for 2 hours.
• the nanoparticle suspension was then removed, the ceils were washed directly three times with PBS 5 and the cells were imaged immediately via fluorescence microscopy with a FiTC filter.
• the n-anopartieies were prepared by an emulsion/solvent evaporation method, Briefly, poly(atearie acid carbonaie-co- ⁇ -caprolacto ⁇ c) was dissolved in 2(J mL dichioromethane. Alternatively, ⁇ oly ⁇ stearic acid carbonate-co- ⁇ -caprolactone) was dissolved in 20 mL dichiororn ethane containing either 1 or 10 wi % pacliiaxel per weight of polymer. The solution was poured into a mixture of 200 mL iki ⁇ ruzed water containing 0.5% w/v SDS.
• Example 23 Nanoparticie Expanding In Acidic. But Not. Neutral Conditio s
• a sample of the nanopartieies from Example I S was diluted in buffer at a pH 4, 5, or 7.4 and maintained at 37 0 C.
• the diameter of the particles was then measured at regular time intervals using dynamic light scattering (DLS), showing bow the particles increased m size over time. Poor to each DLS measurement, the samples were sonicated for 5 seconds to break up aggregates. Particle swelling from 100 nm in diameter to near 1 ⁇ m in diameter was observed (see Fig. 9), hi addition, the release of free 2,4,6- trimethoxyfae ⁇ xa ⁇ dehyde was observed using U YVYi s spectroscopy at a wavelength of 292 nm, also indicating deprotection of the polymer side groups (see Fig. ! Q).
• Nanopartides were prepared from the resulting product by methods described herein.
• a sample of the nanopartieks was diluted in 0.1 M HCI and maintained at 25 0 C.
• the diameter of the panicles was then measured at regular time intervals using dynamic light scattering CDLS), showing how the particles increased in size over time (Fig. 12).
• Fig. 12 shows thai at a pH of about 1.0, the particle size changes from about 200 nm to about 1600 nr ⁇ over the course of about 24 hoars, whereas at a pH of about 3.0, the particle size is stable over the same time period,
• Polymer films were cast onto glass by depositing a polymer soluu ' o. ⁇ comprised of an individual copolymer including but not limited to poly(siearic acid carbonate- co- ⁇ - capralaetenc), dissolved in dichlorometriarse, tetrahydrofura ⁇ , or toluene, using a rmerosyrmge. 11>e solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours.
• a polymer soluuu ' o. ⁇ comprised of an individual copolymer including but not limited to poly(siearic acid carbonate- co- ⁇ - capralaetenc), dissolved in dichlorometriarse, tetrahydrofura ⁇ , or toluene, using a rmerosyrmge. 11>e solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours.
• Example 2.6 Formation of Multi-layered Polymer Films Poly( stearic acid carbonato-co- ⁇ -caproiacto ⁇ ie) films were adhered between polyClactic-C ⁇ -glyeotie acid) dims. A ⁇ o!y(Iactic-co-glyeoiic acid ⁇ /dicMoromeiha ⁇ e solution was deposited onto glass using a r ⁇ ierosyringe to form a film, A po!y(stearic acid ca ⁇ boi ⁇ at.e-co- ⁇ -caproiactoi ⁇ e)/dichloromethane solution was deposited onto the poly ⁇ Iactic-co-glycolic acid) film using a microsyri ⁇ ge to form a second layer.
• a poly(lactic-co-glycoiic acid ⁇ /dichloro ⁇ netha ⁇ ie solution was deposited onto tJie poly poly(stcaric acid carbunate-co-K-caprolactone) film using a rnicrosyringe to form a third laver.
• Patterned drug loaded polymeric films were cast onto glass by using a microprinter or microsyringe by depositing a polymer solution of poly( stearic acid carbonate-co- ⁇ -eaproiactone), dichioromethane. and lO-hydroxycamptotheein, in a controlled manner to form patterns such as stripes and dots.
• the solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours. This method can also be used with more than one polymer simultaneously.
• Exajrvpk_3 ⁇ _lj$e ⁇ Drug- loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly(caproiaetcme ⁇ (5 mg), diehloromethane (50 uL), and K ) - hydrosycampioihecin (100 ⁇ g), using a microsyringe, Tm solvent was removed by slow evaporation over night, and then placed under reduced pressure for 24 hoars. An initial burst was seen over the first two days, releasing at a rate of about 5 ⁇ g/day.
• Drug-loaded polymer films were also cast onto glass by depositing a polymer solution comprised of poty(stearie earborsate-eo- ⁇ -eaprolactoBe) (5 mg), diehlotomethane (50 ⁇ L ⁇ , and paciitaxel (100 ⁇ g), using a miero.syri.nge.
• the solvent was removed by- slow evaporation over night and then placed under reduced pressure lor 24 hours.
• the resulting films were homogenous and opaque, with good adherence to the glass substrate.
• Drug-loaded polymer films were east onto glass by depositing a polymer solution comprised of poly( stearic acid carbotiate-co- ⁇ -eaproiaetcme) i5 mg), dichloroinethane- (50 ⁇ L ⁇ , and l O-bydroxycamplotlieciii (100 ⁇ uj, using a niierosyring ⁇ .
• the solvertt was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. A slight initial burst was seen over the first two days, releasing at a rate of about 3 ⁇ g/day. Continuous release occurred over at least 30 days at a nearly constant rate of about 1 ⁇ g/day.
• drug-loaded polymer films were east onto glass by depositing a polymer solution comprised of po ⁇ yi ' stea ⁇ c carbonate-co- ⁇ -caprolactone) (5 mg), diebloromethane (50 ⁇ L), and paciitaxel (1 (K) ⁇ g), using is mierosyringe. The solvent was removed by skrw evaporation overnight and then placed under reduced pressure for 24 hours. The resulting films were homogenous and opaque, with good adherence to the glass substrate. The films released taxol over time.
• Drug- loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly(hydroxy glycerol carbo ⁇ ate-co- ⁇ -caprolaetone) (5 Big), diehlorometliane (50 ⁇ L), a ⁇ d 10-hydroxycamptomedn (100 ⁇ g), using a micros yringe.
• the solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hows, An initial burst was seen over the first day, releasing at a rate of about 18 ⁇ g/day. Continuous release occurred over at least 30 days, hegbmng at a rate of 3 ⁇ g/day and slowly decreasing to less than 1 ⁇ g/day at four weeks.
• Example 33 In Vitro Tumor Cytoxieity with Paciitaxel-toaded
• Lewis Lung Carcinoma (LLC) cells were washed with sterile phosphate buffered saline (PSS) and trypsinized. The cells were then counted using a Coulter counter and plated 3,000 cells/well m 96 well plates. Cells were serum starved overnight and then treated with empty nanoparticies, pad itax el-loaded nanoparticles (10% paelitaxel), and paeliiaxel-ioaded nanop&rtieles (1 % paclitaxel) for a five day period. A positive control contained 10% FBS or the same concentration of FBS provided for treated cells, while a negative control lacked FSS.
• PSS sterile phosphate buffered saline
• the cells were incubated with 50 ⁇ L of I x Thiazolyl Blue Tetra ⁇ olmm Bromide (MTT, Sigma) dissolved in FBS at 37 0 C for two hours.
• the .media was then aspirated and 100 ⁇ .L of DMSO was added to each well,
• the plates were then placed on a shaking device for 10 minutes and the wells turned purple, corresponding wife the numbers of viable mitochondria in the well.
• the plates were placed on an ELISA reader and scanned at a wavelength of 570 nm, The absorbanee values were normalized to values from a known number of stained cells. No cytotoxicity was observed with the empty naxioparticlcs (as a control. H(X ? ⁇ , whereas cytotoxicity was observed with the taxol loaded nanopartides, as shown m Figs. 4 ami 5.
• Example 34 Release of t Q-Ii ydroxycainptothecin from PolyCdauric, ⁇ iyristsc, palmitic, or stearic). glycerol carbonate-co-s-eaprolactone)
• Drug-loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly((faime, rayristie, palmitic, or stearic) earbonate-co-s-caprolaetone) (5 Big), dkhloromeiha ⁇ e (50 ⁇ L), and 10-hyd ⁇ oxvcamptothecin (100 ⁇ g). using a ⁇ iicrosyri ⁇ ge. The solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. An initial burst was seers over the first day, releasing at a rate of about S-IO ⁇ g/day.
• Drug-loaded polymer films were cast onto pericardium by depositing a p ⁇ fv ⁇ ner solution comprised of poiy(stearic acid carlxmate-co- ⁇ -eaprolactone) (5 nig), dichlorometha ⁇ e (50 ⁇ L), and 10-hy ⁇ roxycamptothecm (100 ⁇ g), using a microsyringe. The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours. An initial burst was seen over the first day, releasing at a rate of about. LO ⁇ g/day. Continuous release occurred over at least 40 days, beginning at a rate of 3 ⁇ g/day ant! slowly decreasing to less than ! ⁇ g-day at four weeks (see Fig. 7).
• Example 36 Cell Culture and Cell Proliferation Assays Melanoma Bl 6 ⁇ murine). Calu 6 (human lung carcinoma), A549 (human lung carcinoma), and LLC' (murine Lewis Lung Carcinoma) were incubated (3? f 'C, 5% €CVs with MEM ⁇ with 10% fetal bovine serum (FBS) and 1 % essential amino acids. The media was change once every three days. When not cultured, all. cell lines were stored m itPMI ireezmg media at -80 0 C (with 50% FBS, 40% RPMi ami 1.0% dimethyl sulfoxide (DMSO)). Cell lines were trypsim ⁇ xx!
• the ceils were incubated with 50 ⁇ l of 1 x Thiazoiy! Blue Tettazolium Bromide (MTT, Sigma) dissolved in PBS at 37 3 C tor two hours. The media was then aspirated and 100 ⁇ l of DMSO was added to each well. The plates were then placed on a shaking device for 10 minutes and the w ⁇ lb turned purple, corresponding with the numbers of viable mitochondria in the well. The plates were placed on an EIJSA reader asid scanned at a wavelength of 570 nm. The absorbance values were normalized to values from a kaowa number of stained cells.
• CeI! proliferation assays testing the effects of paciitaxei were performed using three tumor ceil lines, Lewis Lung Carcinoma (LLC), Melanoma and Caks ⁇ (ramian lung cancer) ceil lines were plated at 3,000 cells/well and when established, cultured in .media with/without paelitaxeL Some cultures were maintained with optimal growth factors
• Ceil proliferation assays were utilized to study the effects of paclitaxd-loaded micropartieies on tumor growth. Tumor cells were plated at 3000 cells/well and positive (serum-rich) and negative (serum-poor) cultures were used to signify 0% and 100% growth inhibition respectively. It was found that the addition of 100,000-500,00O micropaiticles/nil results m inhibition equal to paelitaxel concentrations of --10 ng/mL despite the presence of serum rich media. Inhibition of tumor growth was not present with control (DMSO) microparticles that do not contain paciitaxeL These results demonstrate that paclitaxe! -loaded microparticles are an effective means of drug delivery and specifically result in an effective a ⁇ ti- tumor response in vitro.
• DMSO control
• a cell proliferation assay comparing paciitaxel-l ⁇ aded microparticles and DMSO (control) roicropartici ⁇ s using the melanoma cell line was run for five consecutive days with s plate undergoing MlT analysis each day for days 2-5.
• Paelitaxel loaded micropa ⁇ ieles and DMSO micropartides were added to serum rich media and individually assessed on tumor cells of the same plate. The results demonstrate a dose-dependem inhibition with the admmistrsticrs of paciitaxe!
• Example 38 Naaopaniele Uptake by Cells Fluorescent nanoparticles were created as describe herein with the addition of 2 mol% of a fluorescent co-rao ⁇ omer.
• Non-small cell lung cancer A549 cells were seeded onto a 96- well piste (20,000 ceils/ well) and incubated overnight at 37 " J C and 5% e&rboii dioxide, ' The media was then removed from the wells and replaced w.h a buffered saline solution containing fluorescent nanoparticles at a concentration of 0.5, 1. or 5 mg/rnL. Controls not containing ⁇ anopartic ⁇ cs were also performed.
• the particle suspension was removed, and the cells were washed twice with buffered saline and then iysed with 10(1 ⁇ .L of 0.5% Triton X-HJ0 ⁇ in 0.2 M sodium hydroxide. Measuring the fluorescence of the cell lysale samples (excitation wavelength ⁇ 470 nm, emission wavelength ::: 518 n ⁇ s) and comparing to a standard curve gave tie concentration of nanoparticies in the samples. The cells showed increasing uptake over time and with decreased nanoparticle eonceritnUiori in the buffer,
• Example 40 j > enietrexed./ «.
• PBS sterile phosphate buffered saline
• Hie cells were then counted using a Coulter counter and plated 3,000 eelis/weil in 96 well plates. Cells were serum starved overnight and then treated with per ⁇ etrexed, contra! poly ⁇ hydroxy glycerol carbonate-co-t-caprolactone) micropartides or pemetrexed loaded poiy(hydroxy glycerol carbonate-eo-e-caprolacto ⁇ e) microparticies the next day.
• a positive control contained 10% FBS or the same concentration of FBS provided for treated CeHs 5 while a negative control lacked FBS, At the completion of the assay the cells were incubated with 50 ⁇ l of 1 x Thiazoly!
• Example 42 In K ⁇ Tumor Cytoxicity with Paclitaxd-ioadcd NanoparUcjgs Cultured tumor eel! lines for lung (murine TXC and human A549 and NCI-R460 ⁇ , melanoma (Bl ⁇ ), mesothelioma (human MSTO-21 111), breast (human MCF?), human esophageal sarcoma (LM SOS) cancers were cultured at 37 0 C / 5% CO> in the appropriate media supplemented with 10% Fetal Bovine Serum (FBS) &n ⁇ i% penicillin/streptomycin with t-ghsiarome, with the exception of MEM media which also contained 1% essential amino acids and I mg/mL of bovine insulin.
• FBS Fetal Bovine Serum
• penicillin/streptomycin with t-ghsiarome
• BB cell Hoe was seeded at concentrations of 3,000 (LLC, B ⁇ C>, A549, MSTO-21 ⁇ H, NC1-H46U), 5,000 (MCF7) or 10,000 (LMSO5) cells/well into 96-well assay plates in order to establish the appropriate tumor cell plating density.
• Cells were co-euitured for 7 days with paelitaxd- ioaded and imloaded 5-methy1-2- ⁇ 2,4,6-trimethoxyphenyl)-l,3- ⁇ .iioxan-5-y1-iT ⁇ ethyi methaerylate nanopartides (fabrication described above). After the incubation period, cells were assayed for viability via MIT analysis and plotted as the percentage of viable ceils using a positive control (culture containing no nanopartkles) to rep.rese.nt 100% viability.
• FIG. 18 shows the anti-cancer activity of pac ⁇ t ⁇ xef loaded nanopailicie witli LLC cells in vifro.
• Example 43 Quai ⁇ tiii cation of Mieropartiele Adherence to Lung
• PlXiA rmcropartseJes were suspended in Pluronic NF-127 or water ami each solution was painted onto the intact mouse lungs. The lungs were rocked side-to-side in PBS, simulating the eoLiting of pleural fluid, for differing time periods and the percent of adherent mieropartiebs was determined using a coulter counter.
• Lewis Lung Carcinoma cells 750,000 were injected with or witiioui 50 million PLGA-Paclitaxel loaded microparticies subcutaneous! y in C57BL6 mice. It is well established that this tumor dose results in subcutaneous tumor nodules within 1 week with rapid growth requiring sacrifice within 2-3 weeks. In the time following injection it was found that asmor size was significantly decreased in animals receiving LLC cells and PLGA-paditaxel microparticies vs. LLC cells alone. Ai.
• Example 46 Anti-T ⁇ n ⁇ r Response of Subcutaneous Polymer Film Implantation In Vivo 5
• the anti-tumor effects of chemotherapy-loaded polymer film implants were also evaluated using a subcutaneous tumor model. After induction of anesthesia, C57BL/6 mice were shaved and skin on the hack of the mouse was pr ⁇ pp ⁇ d in a sterile fashion. An incision of 0.8 em was made between the shoulders of the mice. The connective tissue under the skin was dissected with a pair of sterilized tweezers to make a subcutaneous pocket, A piece of sterilized polymer .film dried on a pericardium strip (O.S x.
• Tumor size was monitored biweekly and animals were euthanized if tumors reached 2 cm in size.
• Tumor growth aid not occur overtop of polymer films loaded with 30 ⁇ g i ⁇ -hydroxycampiothecin (1 (MiCPT) in any of the experimental mice (see Fig. 14). This is hi contrast to the significant tumor growth thai occurred directly on the unloaded polymer iiims in over 75% of the animals tested.
• Some animals that had received I 0- HCPT loaded polymer films did develop tumors with delayed foliow- ⁇ p but these tumors were always in the periphery of the pocket and away from the film Itself (see Fig. ⁇ S).
• these tumors were significantly smaller in size (p ⁇ 0,005), confirming that the i0-HCPT loaded films prevented and/or delayed local tumor growth in the in vivo tumor model .
• Example 47 Ko Delay M ..Wound Healing In the . Presence of Subcutaneous
• Polymer iiims were subcutaneously implanted on the back of C57BL/6 " mice under anesthesia as described herein. Healing was assessed by inspection in animals that received 1 (M-ICPT loaded polymer films, unloaded polymer iiims or sham surgery where subcutaneous pockets were prepared but no film was implanted. All incisions were closed with S-O suture. There was no evidence of wound dehiscence early or late (up to 21 days) m animals that received loaded or unloaded films, in addition, there was no difference in erythema or wound appearance among animals with films versus sham surgery.
• the local drug release pattern of subciuaneousiy implanted drug-loaded polymer films in vivo was examined. Polymer films were subcutaneously implanted on the back of C57BL/6 mice under anesthesia as described above. At weekly intervals following implantation of the films, the surrounding tissues were harvested. These tissues were cut in a radial fashion away from the film and sequentially segmented at I mm distances away from the film, thus providing tissue for assessment at various distances and directions away from the drug-loaded film. The concentration of the drug eluted at the various distances was then ascertained within each tissue segment using MPLC for the specific drug of interest. The gradient of drag concentration within a 2 em diameter of the center of the film was then plotted to establish the drug release kinetics and drug distribution into the surrounding tissues in vivo.
• Example 50 In Vivo Intraperitoneal Mesothelioma Animal Experinu-rst with
• Paditaxel-Loaded NanoparUdes The abi lity of drug-loaded nanoparticles to inhibit the growth of human tumor cells in vivo within the intraperitoneal cavity has also been investigated using a murine model of mesothelioma using a well established in vivo tumor model ⁇ Adusu ⁇ JU et ⁇ • /., J Thorac Cardiovasc Sarg. 132:1 ! 79-88, 2006).
• Cultured mesothelioma tumor cells (5 million MSTO-21 I H) were co-injected with paclitaxel-loaded fcnctional nanoparticles via an i.p. injection into the lower abdomen of NLVJ (nude) mice.
• naiioparticles Animals injected with tumor cells alone in PBS or tumor with identical doses of loaded r.on-functional (non- expansile) naiioparticles served as consols for tumorigenieity and ⁇ anoparticle. toxicity, respectively.
• Example 51 SEM of Films Drug-loaded polymer films were cast onto glass by depositing a polymer solution comprised of polyC ' slearic earbonate-co- ⁇ -caprolaetone) (5 nig), dichloromiihane (50 ⁇ t), and I O-hydroxyearnpioiht'cin (100 ⁇ g), using a micro syringe. The solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. Prior to imaging, the films were coated with 7 am of Aa/Pd. The films were imaged using scanning electron microscopy. The surfaces of the films appeared smooth and non- porous with fshrous-lske mierotexiure. As shown in Rg, S, cross-section images also revealed a smooth, non-porous interior with consistent thicknesses throughout She length of the film of approximately 40 microns.
• Samples for scanning electron microscope (SEM) imaging were prepared by diluting a sample of nanoparticles io a concentration of 0.25 mg/mL with deionked water, A 10 ⁇ L portion of the diluted sample was then placed on a clean aluminum stub ami allowed to air dry. Prior to imaging, the samples were coated with a 5 rim layer of Au-Pt. Samples were then imaged on a Zeiss SUPRA 40VP Held emission SUM using an accelerating voltage of 1 kV. ' The image in Fig. ⁇ 1 shows particles from about 1 to 50 microns with most of the particles between 5 and 20 microns.
• Example 53 Contact. Angle Measurements Polymer films were cast onto glass substrates and the contact angle of each film was determined using contact angle goniometry. Contact angles ranged from 75 ⁇ • 120". For example, the contact angle of polyCsieai ⁇ c acid earbonatc-co- ⁇ -caproiacto ⁇ ie ⁇ was 1 1 ⁇ 'l The contact angle of glass is about 35°.
• Example 54 Thermal Transition Measurements
• Thermal transitions of each polymer were measured using differential scanning calo ⁇ metry.
• Polymers composed of ⁇ -caprolactone and be ⁇ zyloxy glycerol carbonate monomers were formed with the following carbonate mole fractions: 0,05, 0.10, 0.20, 0.30, 0.40, 0.50, 1.00.
• Glass transition temperatures ranged from -64 X to -10 0 C and melting temperatures ranged from 22 0 C ⁇ 5? "C.
• Some copolymers were semi- crystailine and other copolymers were amorphous.

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