US20050220880A1 - Drug carriers comprising amphiphilic block copolymers - Google Patents

Drug carriers comprising amphiphilic block copolymers Download PDF

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US20050220880A1
US20050220880A1 US10/506,805 US50680505A US2005220880A1 US 20050220880 A1 US20050220880 A1 US 20050220880A1 US 50680505 A US50680505 A US 50680505A US 2005220880 A1 US2005220880 A1 US 2005220880A1
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Andrew Lewis
Steven Armes
Andrew Lloyd
Jonathan Salvage
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Biocompatibles UK Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00—Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent

Definitions

  • AB diblock copolymers and ABA triblock copolymers A being the hydrophilic block and B being the hydrophobic block have been investigated.
  • the hydrophilic blocks have been provided by polyethylene oxide moieties.
  • the hydrophobic block may be a polypropylene oxide block, a hydrophobic polypeptide (such as poly( ⁇ -benzyl-L-aspartate)), a polyester (poly(DL-lactic acid)) or poly( ⁇ -caprolactone).
  • Polystyrene and poly(methylmethacrylate) have also been investigated as constituents of the core.
  • Suitable ethylenically unsaturated zwitterionic monomers have the general formula Y B X I in which Y is an ethylenically unsaturated group selected from H 2 C ⁇ CR—CO-A-, H 2 C ⁇ CR—C 6 H 4 -A 1 -, H 2 C ⁇ CR—CH 2 A 2 , R 2 O—CO—CR ⁇ CR—CO—O, RCH ⁇ CH—CO—O—, RCH ⁇ C(COOR 2 )CH 2 —CO—O,
  • W 1 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W 1 optionally contains one or more fluorine substituents and/or one or more functional groups; and
  • Monomers in which X is of the general formula in which W + is W 1 N ⁇ R 3 3 may be made as described in our earlier specification WO-A-9301221.
  • Phosphonium and sulphonium analogues are described in WO-A-9520407 and WO-A-9416749.
  • a group of the formula II has the preferred general formula III where the groups R 5 are the same or different and each is hydrogen or C 1-4 alkyl, and m is from 1 to 4, in which preferably the groups R 5 are the same preferably methyl.
  • X may have the general formula IV in which A 5 is a valence bond, —O—, —S— or H—, preferably —O—;
  • X may be a zwitterion in which the anion comprises a sulphate, sulphonate or carboxylate group.
  • s is 2 or 3, more preferably 3.
  • a zwitterion having a carboxylate group is a carboxy betaine —N ⁇ (R 13 ) 2 (CH 2 ) r COO ⁇ in which the R 13 groups are the same or different and each is hydrogen or R 1-4 alkyl and r is 2 to 6, preferably 2 or 3.
  • a particularly preferred zwitterionic monomer is 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt (MPC). Mixtures of zwitterionic monomers each having the above general formula may be used.
  • the hydrophobic block may be formed of condensation polymers, such as polyethers, polyesters, polyamides, polyanhydrides polyurethanes, polyimines, polypeptides, polyureas, polyacetals, polysaccharides or polysiloxanes.
  • condensation polymers such as polyethers, polyesters, polyamides, polyanhydrides polyurethanes, polyimines, polypeptides, polyureas, polyacetals, polysaccharides or polysiloxanes.
  • polyalkylene oxide usually polypropylene oxide
  • Another is polyethylenimine, copolymers of which with polyalkylene oxides have been investigated as drug delivery components.
  • One type of highly hydrophobic block is poly(dimethylsiloxane).
  • the type of polymer forming the hydrophobic block is the same as that forming the hydrophilic block.
  • the polymer is formed by radical polymerisation of ethylenically unsaturated monomers.
  • the hydrophobic block comprise pendant cationisable moieties preferably as pendant groups.
  • Cationisable moieties are, for instance, primary, secondary or tertiary amines, capable of being protonated at pH's in the range 4 to 10.
  • the group may be a phosphine.
  • Suitable monomers from which the hydrophobic block may be formed have the general formula VII Y 1 B 1 Q VII in which Y 1 is selected from H 2 C ⁇ CR 14 —CO-A 8 -, H 2 C ⁇ CR 14 —C 6 H 4 -A 9 -, H 2 C ⁇ CR 14 —CH 2 A 10 , R 16 O—CO—CR 14 ⁇ CR 14 —CO—O, R 14 CH ⁇ CH—CO—O—, R 14 CH ⁇ C(COOR 16 )CH 2 —CO—O,
  • Y 1 is H 2 C ⁇ CR 14 —CO-A 8 - where R 14 is H or methyl and A 8 is O or NH.
  • Preferred groups B 1 are alkanediyl, usually with linear alkyl chains and preferably having 2 to 12 carbon atoms, such as 2 or 3 carbon atoms.
  • Q is NR 17 2 where R 17 is C 1-12 -alkyl.
  • R 17 'S are the same. Particularly useful results have been achieved where the groups R 17 are C 1-4 alkyl, especially ethyl, methyl or isopropyl.
  • R 21 is a C 1-10 alkyl, a C 1-20 alkoxycarbonyl, a mono- or di-(C 1-20 alkyl) amino carbonyl, a C 8-20 aryl (including alkaryl) a C 7-20 aralkyl, a C 6-20 aryloxycarbonyl, a C 1-20 -aralkyloxycarbonyl, a C 6-20 arylamino carbonyl, a C 7-20 aralkyl-amino, a hydroxyl or a C 2-10 acyloxy group, any of which may have one or more substituents selected from halogen atoms, alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine (including mono and dialkyl amino and trialkylammonium in which the alkyl groups may be substituted), carboxyl, sulphonyl, phosphoryl, phosphino, (including mono and di-allyl phosphin
  • the block copolymers should have controlled molecular weights. It is preferable for each of the blocks to have molecular weight controlled within a narrow band, that is to have a narrow polydispersity.
  • the polydispersity of molecular weight should, for instance, be less than 2.0, more preferably less than 1.5, for instance in the range 1.1 to 1.4.
  • Block copolymer it may be possible to synthesise the block copolymer by initial formation of a low polydispersity, low molecular weight initial block using control of initiator and chain transfer agent (which permanently terminates chain formation), with the initial block then being derivatised to act as a suitable radical initiator in a subsequent block forming step, by the technique described by Inoue et al op. cit.
  • Low polydispersity low molecular weight polymers which may be derivatised to form a substrate for the block polymerisation of second block are commercially available.
  • Such polymers are, for instance, poly(alklylene oxides), poly(dimethyl siloxanes), polyimides, acrylic copolymers, etc.
  • oligomers are derivatised to form initiator compounds for controlled radical polymerisation are described below.
  • the polymerisation of at least one of the blocks and preferably both the blocks is by controlled radical polymerisation for instance a living radical polymerisation process.
  • the initiator has a radically transferable atom or group
  • the catalyst comprises a transition metal compound and a ligand, in which the transition metal compound is capable of participating in a redox cycle with the initiator and dormant polymer chain, and the ligand is either any N-, O-, P- or S-containing compound which can coordinate with the transition metal atom in a ⁇ -bond, or any carbon-containing compound which can coordinate with the transition metal in a ⁇ -bond, such that direct bonds between the transition metal and growing polymer radicals and not formed.
  • the initiator may be di, oligo- or poly-functional, which may be of use to form A-B-A type copolymers or star polymers.
  • a suitable initiator is based on various considerations. Where the polymerisation is carried out in the liquid phase, in which the monomers are dissolved, it is preferable for the initiator to be soluble in that liquid phase. The initiator is thus selected for its solubility characteristics according to the solvent system which in turn is selected according to the monomers being polymerised.
  • Water-soluble initiators include, for instance the reaction product of monomethoxy-capped oligo(ethylene oxide) with 2-bromoisobutyryl bromide (OEGBr), 4-bromo- ⁇ -toluic acid or ethyl 2-bromopropanoic acid or 2-(N,N-dimethylamino) ethyl-2′-bromoisobutyrate.
  • OEGBr 2-bromoisobutyryl bromide
  • 4-bromo- ⁇ -toluic acid or ethyl 2-bromopropanoic acid or 2-(N,N-dimethylamino) ethyl-2′-bromoisobutyrate 2-bromoisobutyryl bromide
  • the portion of the initiator —C—R 24 R 25 R 26 becomes joined to the first monomer of the growing polymer chain.
  • the group X 2 becomes joined to the terminal unit of the polymer chain.
  • Selection of a suitable initiator is determined in part by whether a terminal group having particular characteristics is required for subsequent functionality. Subsequent reactions of the product polymer are described below.
  • the residue of the initiator at one or other end of the polymer may be reacted with biologically active moieties, such as targetting groups.
  • the initiator itself may comprise a group conferring useful targeting or other biological activity in the product polymer.
  • the initiator may comprise a highly hydrophobic group, which is polymeric and which may consequently form the part of the hydrophobic block.
  • Suitable hydrophobic polymers which may be converted into initiators are, for instance, poly(propylene oxide) and poly(dimethyl siloxane).
  • the transition metal compound which comprises a component of the catalyst is M t n+ X 3 n , where:
  • X 3 is halide, most preferably chloride or bromide.
  • Particularly suitable transition metal compounds are based on copper or ruthenium, for instance CuCl, CuBr or RuCl 2 .
  • the ligand is preferably selected from the group consisting of:
  • a suitable ligand is, for instance, based upon the solubility characteristics and/or the separability of the catalyst from the product polymer mixture. Generally it is desired for the catalyst to be soluble in a liquid reaction mixture, although under some circumstances it may be possible to immobilise the catalyst for instance an a porous substrate. For the preferred process, which is carried out in the liquid phase, the ligand is soluble in a liquid phase.
  • the ligand is generally a nitrogen containing ligand.
  • Such ligands are usefully used in combination with copper chloride, copper bromide and ruthenium chloride transition metal compounds as part of the catalyst.
  • a living radical polymerisation process is preferably carried out to achieve a degree of polymerisation in the or each block in the range 2 to 2000.
  • the degree of polymerisation is in the range 5 to 1000, more preferably in the range 10 to 100.
  • the degree of polymerisation is directly related to the initial ratios of initiator to monomer.
  • the ratio is in the range 1:(2 to 2000), more preferably in the range of 1:(5 to 1000), most preferably in the range 1:(10 to 100).
  • the ratio of metal compound and ligand in the catalyst should be approximately stoichiometric, based on the ratios of the components when the metal ion is fully complexed.
  • the ratio should preferably be in the range 1:(0.5 to 2) more preferably in the range 1:(0.8:1.25). Preferably the range is about 1:1.
  • the catalyst may be used in amounts such that a molar equivalent quantity as compared to the level of initiator is present. However, since catalyst is not consumed in the reaction, it is generally not essential to include levels of catalyst as high as of initiator.
  • the ratio of catalyst (based on transition metal compound) to initiator is preferably in the range 1:(1 to 50), more preferably in the range 1:(1 to 10).
  • the polymerisation reaction may be carried out in the gaseous phase, it is more preferably carried out in the liquid phase.
  • the reaction may be heterogeneous, that is comprising a solid and a liquid phase, but is more preferably homogeneous.
  • the polymerisation is carried out in a single liquid phase.
  • the monomer is liquid, it is sometimes unnecessary to include a nonpolymerisable solvent. More often, however, the polymerisation takes place in the presence of a nonpolymerisable solvent.
  • the solvent should be selected having regard to the nature of the zwitterionic monomer and any comonomer, for instance for its suitability for providing a common solution containing both monomers.
  • the solvent may comprise a single compound or a mixture of compounds.
  • the zwitterionic monomer is MPC
  • water should be present in an amount in the range 10 to 100% by weight based on the weight of ethylenically unsaturated monomer.
  • the total nonpolymerisable solvent comprised 1 to 500% by weight based on the weight of ethylenically unsaturated monomer. It has been found that the zwitterionic monomer and water should be in contact with each other for as short a period as possible prior to contact with the initiator and catalyst. It may be desirable therefore for all the components of the polymerisation other than the zwitterionic monomer to be premixed and for the zwitterionic monomer to be added to the premix as the last additive.
  • MPC copolymerise MPC or other zwitterionic monomer with a comonomer which is insoluble in water.
  • a solvent or co-solvent in conjunction with water is included to confer solubility on both MPC and the more hydrophobic monomer.
  • Suitable organic solvents are ethers, esters and, most preferably, alcohols.
  • suitable alcohols are C 1-4 -alkanols. Methanol is found to be particularly suitable in the polymerisation process of the invention.
  • the process may be carried out at raised temperature, for instance up to 60 to 80° C. However it has been found that the process proceeds sufficiently fast at ambient temperature.
  • the living radical polymerisation process has been found to provide polymers of zwitterionic monomers having a polydispersity (of molecular weight) of less than 1.5, as judged by gel permeation chromatography. Polydispersities in the range 1.2 to 1.4 for the or each block are preferred.
  • a new method of forming an aqueous composition comprising an amphiphilic block copolymer and a biologically active compound, in which the copolymer comprises a hydrophilic block and a hydrophobic block an aqueous dispersion of empty copolymer micelles is formed and the micellar dispersion is contacted with biologically active compound under conditions such that the biologically active compound becomes associated with the copolymer in the micelles, characterised in that the hydrophilic block has pendant zwitterionic groups.
  • composition of the invention comprises micelles of block copolymer with biologically active molecule in the core
  • this may be formed by a variety of techniques.
  • the process may involve simple equilibration of the drug and polymer micelles in water, at a concentration above the critical micelle concentration (CMC) of the block copolymer.
  • CMC critical micelle concentration
  • drug may be contacted in solid form with an aqueous dispersion of polymer micelles and incubated, optionally with shaking, to solubilise the active in the dispersed micelles.
  • drug dissolved in organic solvent may be emulsified into an aqueous dispersion of polymer micelles, whereby solvent and biologically active compound become incorporated into the core of the micelles, followed by evaporation of solvent from the system.
  • An advantage of the present invention where the hydrophobic block is pH sensitive is that micelles may be loaded using a pH change system.
  • polymer is dispersed in aqueous liquid in ionised form, in which it solubilises at relatively high concentrations without forming micelles.
  • the pH is changed such that some or all of the ionised groups become deprotonated so that they are in nonionic form.
  • the hydrophobicity of the block increases and micelles are formed spontaneously.
  • the loading process may involve a temperature change around the transition temperature.
  • Micelles may be loaded by contacting the empty micellar composition with biologically active, either in solid form or in dissolved form in an organic solvent. Solvent may optionally be removed in a subsequent step, e.g. by evaporation, It is found that loading of a model hydrophobic drug from a film on the inner surface of a vessel containing the empty polymer micelles generated micellised drug after reasonable periods.
  • Taxotere 5.86 6-Thioguanine 167 ⁇ 0.28 Tirofiban 0.46 440.6 Topotecan 1.757 421 Tranilast ⁇ 1.09 327.3 Vinblastine 814 1.68 Cancer Chemother Pharmacol 20/4/763/1990 Vincristine Sulfate 923 2.14 Cancer Chemother Pharmacol 26/4/263/1990
  • Micellised drug delivery systems have been used for cytotoxic drugs, for instance used in anti-cancer and/or antiangiogenic therapies, and such drugs may be used in the present invention.
  • examples are doxorubicin, daunomycin and paclitaxel and analogues and derivatives thereof.
  • FIGS. 1 and 2 indicate the results of example 3.
  • FIG. 3 illustrates the effect of pH on the solubilisation of a hydrophobic drug for block copolymers used in the invention.
  • FIG. 4 shows the results of Example 4.
  • FIGS. 5 to 7 shows the results of Example 5.
  • FIG. 8 shows the results of Example 6
  • FIG. 9 shows the results of Example 8.
  • FIGS. 10 to 12 shows the results of Example 9
  • FIGS. 13 and 14 show the results of Example 10.
  • FIGS. 15 to 17 show the results of Example 11
  • FIGS. 18 a and 18 b show the results of Example 12
  • FIGS. 19 and 20 show the results of Example 13
  • FIGS. 21 to 23 show the results of Example 15.
  • A-B block copolymers were formed by an atom transfer polymerisation with MPC being homopolymerised in a first block forming step using an oligo(ethylene glycol) initiator as described by Ashford E. J. et al in Chem. Commun.
  • the reaction mixture was diluted with methanol and passed through a silica column to remove residual ATRP catalyst. After solvent evaporation, the products were dried under vacuum at room temperature.
  • Relatively monodisperse macroinitiators of a variety of different hydroxy-terminated polymers can be made by reaction of the terminal OH with 2-bromoisobutyryl bromide according to (scheme 1).
  • the resulting macroinitiators are used in the synthesis of block copolymers (examples shown in Table 2) by the method outlined in Example 1.
  • the components were used in amounts as follows MPC (6.0 g, 2.02 ⁇ 10 ⁇ 2 mol).
  • the molar ratios of MPC:initiator:Cu(I)Br:bpy was x:y:1:7 where x and y are given in Table 2.
  • the solvent used is indicated in Table 2. TABLE 2 Examples of Block Copolymers Using the Macroinitiator Route.
  • FIG. 1 shows the proton NMR spectra from 0.8 to 1.8 ppm of MPC50-PPO33 with increasing temperature from 5-70° C. Note that the peaks characteristic of the PPO (a) decrease in size and broaden into two, with increasing temperature, whilst that of the MPC backbone moves from a broad, undefined hump, to a more well defined et of peaks. This illustrates that as the temperature is raised, the PPO becomes more hydrophobic and moves to the core of the forming micelles, and vice versa for the MPC, which is in the more solvated outer shell of the micelle structure.
  • One of the blocks of the diblock may be composed of a species of tunable hydrophobicity, for instance a tertiary amine group that can be protonated or deprotonated.
  • a pH-induced micellisation can be observed shown schematically in FIG. 3 .
  • FIG. 5 shows show the dye uptake profile with concentration for MPC30-DEA60.
  • C there was no dye solubilisation
  • A there was dye uptake.
  • B the level of dye solubilisation was greatly reduced in comparison to pH 8 at 37° C.
  • FIG. 6 A comparison of the results for all the MPC-DEA block copolymers at pH 8 and pH 10.8, at 37° C. in McIlvaines buffer, can be seen in FIG. 6 . This shows that by increasing the hydrophobicity of the copolymers, either by increasing DEA block length or raising the pH, that the amount of hydrophobic Orange OT dye uptake is also increased.
  • the results for the MPC-DEA and MPC-DPA polymers were converted to a mol:mol ratio
  • the mol:mol ratio of dye to polymer can be seen in FIG. 8 and it can be seen that the ratio of dye to polymer increases as the pH of the solutions is increased, and as the hydrophobic block (DEA or DPA) is increased in length.
  • the lowest ratio belonged to MPC20-DEA20, with the highest being the MPC100-DPA100.
  • the test are all carried out at 37° C.
  • the particle diameter of the MPC-DEA and MPC-DPA polymers was measured using photon correlation spectroscopy (PCS) with a 10 mW He—Ne laser, a wavelength of 63 nm, and a 90 degree detector angle to the laser.
  • PCS photon correlation spectroscopy
  • Initial work focused on the MPC-DEA polymers, examining particle size in response to pH and temperature. Following the finding that MPC-DEA polymers were not in the micelle form at pH 7.4, the focus was switched to the MPC-DPA polymers which had a more favourable pH profile.
  • the particle diameter (nm) at 5° C., 25° C., and 70° C. for MPC-DEA and MPC-DPA at a number of different pH values can be seen in Tables 3-5.
  • MPC100-DPA100 forms a temperature stable micelle system.
  • pH 4.0 the system is stable and in unimer form from 5° C. to 70° C.
  • pH 7.4 the MPC100-DPA100 is in micelle form and is also stable across the temperature range, and when Orange OT dye was solubilised the particle size increased and continued to be stable from 5° C. to 70° C.
  • micellised polymers The dilution stability of the micellised polymers was monitored using PCS, by preparing the MPC-DPA polymers in McIlvaines buffer, pH 7.4, and measuring the particle diameter of sequential halving dilutions at 25° C. Upon each dilution the number of micelles present was halved, as is evident from the count rate which can be seen to halve each time in FIG. 12 .
  • MPC100-DPA100 micelles were present down to 0.001 mM concentration (as was also the case for MPC30-DPA60, data not shown), as seen in FIG. 12 . It may be that the micelles disassembled at 0.001 mM concentration; alternatively the limit of detectability using PCS may have been reached. 0.001 mM does however correspond with the lower end of the curving CMC graph for MPC-DPA polymers as seen in FIG. 7 .
  • the polymer MPC35-DEA60 at pH 12.0 in water was imaged using Cryo-SEM, and tapping mode AFM.
  • the Cryo-SEM image can be seen in FIG. 13 (in which the bar in the lower right corner is 200 nm), a mixed particle population of approximate diameter 50 nm to 100 nm can be seen.
  • the height phase tapping mode AFM image can be seen in FIG. 14 , particle diameter appears to be predominately of approximately 100 nm (in this figure the scale on the x axis has divisions of 1 ⁇ m).
  • a subsequent PCS measurement of the sample solution gave a particle diameter of 28.2 nm.
  • the larger particle size indicated by AFM and Cryo-SEM imaging may be the result of the sample preparation for each technique.
  • V79 cell based colony formation cytotoxicity assay was used. The test was carried out at 37° C. in DMEM with 2.5% FCS and 1% penstrep P/S. The results from a blank plate of media provided the 100% survival figure, from which the % survival can be calculated for each of the dilutions of the MPC-DPA polymers, and the EC 50 determined.
  • the results for MPC30-DPA60, at pH 7.4 in PBS, can be seen in FIG. 15 , and the EC 50 is 650 ⁇ g/ml.
  • the results for MPC100-DPA000, at pH 7.4 in PBS, can be seen in FIG.
  • FIG. 17 shows the results for a control of PBS without the polymer, the EC 50 is 600 ⁇ g/ml, demonstrating that the EC 50 of the MPC-DPA polymers was the result of the first 50% buffer to media dilution of the assay.
  • the surface tension of solutions of various diblock copolymers were determined using a Kruss K12 tensiometer. These determinations were made under various pH conditions in order to examine the relative surface activity of the various diblock copolymers.
  • FIGS. 18 a and b show typical plots obtained for both a DMA (a) and DEA (b) system.
  • FIG. 18 a shows the results for MPC30-DMA60
  • FIG. 18 b shows the results for MPC30-DEA60.
  • the diblock copolymers show no effect on surface activity at low pH, as the amine groups are protonated and the polymers molecularly soluble in water. At higher pH, the amine groups deprotonate, the amine-containing block becomes more hydrophobic and the polymer shows surface activity, as demonstrated by the drop in surface tension with increasing concentration of the polymer in solution.
  • the MPC 30 -DMA 60 , MPC 30 -DEA 60 and MPC30-DPA 60 , diblocks were molecularly dissolved in turn in doubly-distilled water at pH 2.
  • Pyrene/copolymer solutions were prepared by adding acetone solutions of pyrene into dry 10.0 ml volumetric flasks. After evaporation of the acetone, diluted copolymer stock solutions were added so as to obtain final copolymer concentrations ranging from 1 ⁇ 10 ⁇ 4 to 5.0 g L ⁇ 1 ; the final concentration of pyrene was fixed at 6.010 ⁇ 7 mol dm ⁇ 3 .
  • FIG. 19 shows this difference in the spectra for an MPC-DEA diblock copolymer at different pHs (pH4 and 10). Note the intensity of the I3 peak at 373 nm.
  • FIG. 20 shows the variation in the intensity ratio (I 1 /I 3 ) vs. solution pH for three MPC-based diblock copolymers.
  • micellization was estimated from the reduced I 1 /I 3 ratio, which indicates a more hydrophobic (micellar) environment for the pyrene probe (in the case of the MPC 30 -DMA 60 diblock copolymer, there was very little reduction in the I 1 /I 3 ratio, hence either no micelles are formed under these conditions or the micelles are not hydrophobic enough to ensure efficient pyrene uptake).
  • the critical micellization pH values estimated for the MPC 30 -DPA 60 and MPC 30 -DEA 60 diblock copolymers using this method are pH 5.6 and pH 6.9, respectively. These values correlate quite well with the known pka's of 6.0 and 7.3 for DPA and DEA homopolymer reported by (Bütün et al (Bütün, V.; Armes, S. P.; Billingham, N.C. Polymer, 2001, 42, 5993).
  • the plateau value for the I 1 /I 3 ratio observed at high pH is indicative of the relative hydrophobicity of the micelle cores.
  • the plateau value of approximately 1.15 obtained for the MPC 30 -DPA 60 diblock copolymer micelles is comparable to that observed by Wilhelm et al. for polystyrene-core micelles and suggests that highly hydrophobic micelle cores are formed (Wilhelm, M.; Zhao, C.-L.; Wang, Y.; Xu, R.; Winnik, M. A.; Mura, J.-L.; Riess, G.; Croucher, M. D. Macromolecules 1991, 24, 1033).
  • the micelles formed by the MPC30-DEA diblock copolymer clearly have significantly less hydrophobic character.
  • This hypothesis was supported by further fluorescence studies in order to determine the degree of pyrene partitioning within the micelles.
  • Eisenberg and co-workers was adopted (Astafieva, I.; Zhong, X. F.; Eisenberg, A; Macromolecules 1993, 26, 7339).
  • the DEA and DPA micelle core densities are around 1.0 g cm ⁇ 3
  • the pyrene partition coefficients for the MPC 30 -DEA 60 and MPC 30 -DPA 60 diblock copolymer micelles were calculated to be 3.210 4 and 1.1 10 5 , respectively.
  • the pyrene partition coefficient for the DPA-core micelles is close to the value of 1.9-2.4 10 5 reported for highly hydrophobic polystyrene micelle cores.
  • the MPC-DPA diblocks should form more stable micelles with higher loading capacities for the encapsulation of various ‘actives’ such as hydrophobic drugs.
  • a solution of the drug dipyridamole was used given the intensely coloured nature of the drug allows simple detection.
  • this drug was dissolved to give a fluorescent green-yellow solution.
  • the pH 9-10 the drug was seen to precipitate.
  • a solution (at pH 2) of a triblock copolymer of MPC30-DMA30-DEA40 (mixed tunable hydrophobic diblock) was added to the precipitated drug solution at pH9-10, the drug was rapidly solubilised into the hydrophobic micelle cores that formed to give a classically micellar solution.
  • MPC100-DPA100 was dissolved in ethanol at a concentration of 40 ⁇ g/ml. 100 ml of this solution was added dropwise to 9900 ⁇ l of phosphate buffered saline (PBS) (1 in 100 dilution), pH 7.3, whilst being stirred with a 1 cm magnetic stirrer at maximum RPM setting. (Actual speed of stirring still to be confirmed using a calibrated strobe light). The stirring was continued for 2 minutes following the polymer/ethanol injection, and the sample then bath sonicated for 5 minutes. The 1 in 100 dilution produced a final MPC100-DPA100 concentration of 0.4 mg/ml (0.008 mM).
  • PBS phosphate buffered saline
  • Orange OT dye was dissolved in the ethanol prior to the MPC110-DPA100, at a polymer/dye mol:mol ratio of 1:0.5. This was then injected (1 in 100) into PBS under the same conditions as for the unloaded MPC100-DPA100, to give MPC100-DPA 100 0.4 mg/ml (0.008 mM) with Orange OT at 0.004 mM.
  • PCS photon correlation spectroscopy
  • the effect of polymer concentration on micelle size was examined, by making a series of 50% dilutions with PBS, pH7.3, and measuring particle size using PCS.
  • Temperature effects on the solvent injected MPC100-DPA100 was examined from 5° C. to 70° C., at 5° C. intervals, using PCS to measure particle size.
  • the error bars represent the standard deviations for 6 measurements for each sample.
  • Sample “mean” is the mean of samples n1 to n5 and the error bar represents the standard deviation between the 5 samples.
  • a cell formation cytotoxicity assay is used as described below.
  • the polymers to be tested are prepared in phosphate buffered saline by solvent injection.
  • V79 hamster lung macrophages in DMEM media supplemented with 10% foetal calf serum (FCS) and 1% penstrep (P/S) are seeded at 100 cells in 500 ⁇ l per well of a 24 well plate (Iwaki). These are incubated at 37° C., in 5% CO 2 , for 24 hours.
  • the polymer samples are sterile filtered using 0.45 ⁇ m syringe filters (Nalge Nunc). Dilutions of the polymer solutions are prepared in DMEM supplemented with 2.5% FCS and 1% P/S.
  • a control plate of the DMEM supplemented with 2.5% FCS and 1% P/S is run alongside to provide a 100% survival figure. These are all then incubated at 37° C., in 5% CO 2 , for 5 days. After the 5 days the media is removed and the cells fixed with gluteraldehyde (in house) for 30 minutes. This is then removed, the cells washed with deionised water, and stained with 10% giemsa stain in water, for 30 minutes. The stain is then removed and the cell colonies present in each well counted. By comparing the number of colonies from the test samples against the control sample, a % survival figure can be produced for each polymer concentration and the concentration which reduces colony numbers by 50% (EC 50 ) determined.
  • a kill curve for doxorubicin can be constructed by substituting dilutions of doxorubicin in ethanol for the polymers in the assay above. This enables determination of the EC 50 for doxorubicin.
  • Polymer micelles loaded with doxorubicin can be prepared by solvent injection.
  • the doxorubicin is dissolved in ethanol, and the polymer then dissolved in the ethanol/doxorubicin.
  • Injection of a small volume of the polymer/doxorubicin/ethanol into a larger volume of PBS, for example 1 in 100 dilution, whilst the PBS is stirred results in the formation of doxorubicin loaded polymer micelles. If the loaded micelles are substituted for the polymers in the assay above then the EC50 can be determined.
  • doxorubicin PC-micelles The activity of doxorubicin PC-micelles will be determined using two tumour models.
  • the MAC15A tumour and MAC26 tumour have been widely used in the evaluation of anticancer agents.
  • MAC15A is a poorly differentiated, rapidly growing adenocarcinoma that becomes necrotic, and cells are associated with blood vessels in typical tumour cords.
  • MAC26 is a well differentiated glandular adenocarcinoma with a clear stromal component and well-developed blood supply.
  • tumour-bearing mice Groups of 5 to 10 tumour-bearing mice will be treated with either free doxorubicin at previously established maximum tolerated dose (10 mg/kg, single iv) or doxorubicin-loaded MPC micelles at equivalent dose. Treatment will commence when tumours can be reliably measured by callipers (mean dimensions, 7 ⁇ 10 cm). Therapeutic effect will be measured by twice weekly calliper measurement of the tumour.
  • mice At various time points after administration of free doxorubicin or doxorubicin-loaded MPC micelles, mice will be anaesthetised and blood samples taken via cardiac puncture. Blood samples will be kept at 4° C. until centrifugation (1000 ⁇ g for 5 mins at 4° C.). Samples of tumours will be taken and placed into liquid nitrogen. Pharmacokinetic parameters will be estimated by standard noncompartmental methods. Terminal elimination rate will be calculated using linear regression analysis of the terminal log linear portion of the curve.
  • Doxorubicin Extraction Doxorubicin will be extracted from plasma and tumours based on a method developed by Fraier et al. HPLC with fluorimetric detection. (J. Pharm. Biomed. Anal., 13; 625-633 1995). Samples will then analysed by standard HPLC methods using fluorescence detection. This method is capable of separating several doxorubicin metabolites.

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Publication number Priority date Publication date Assignee Title
US20050123501A1 (en) * 2002-01-16 2005-06-09 Lewis Andrew L. Polymer conjugates
US20050214379A1 (en) * 2004-01-02 2005-09-29 Sandro Mecozzi Encapsulation of chemical compounds in fluorous-core and fluorous-inner-shell micelles formed from semifluorinated-block or fluorinated-block copolymers
US20060069203A1 (en) * 2003-02-05 2006-03-30 Lewis Andrew L Block copolymers
US20060135714A1 (en) * 2003-01-16 2006-06-22 Lewis Andrew L Conjugation reactions
US20060269479A1 (en) * 2005-04-19 2006-11-30 Colton Clark K Amphiphilic polymers and methods of use thereof
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US20070218120A1 (en) * 2005-03-18 2007-09-20 Sungkyunkwan University Foundatin For Corporate Colloboration Ph Sensitive Block Copolymer and Polymeric Micelle Using the Same
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US20090036389A1 (en) * 2002-03-29 2009-02-05 Abbott Laboratories Polymeric Micelle Formulations of Hydrophobic Compounds and Methods
US20100247668A1 (en) * 2009-03-30 2010-09-30 Scott Eliasof Polymer-agent conjugates, particles, compositions, and related methods of use
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US8124128B2 (en) 2005-11-08 2012-02-28 Industrial Technology Research Institute Amphiphilic block copolymers and nano particles comprising the same
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050123501A1 (en) * 2002-01-16 2005-06-09 Lewis Andrew L. Polymer conjugates
US20050163743A1 (en) * 2002-03-07 2005-07-28 Lewis Andrew L. Composition of polymers
US20060069203A1 (en) * 2003-02-05 2006-03-30 Lewis Andrew L Block copolymers
US20060135714A1 (en) * 2003-01-16 2006-06-22 Lewis Andrew L Conjugation reactions
US7300990B2 (en) * 2000-10-06 2007-11-27 Biocompatibles Uk Limited Zwitterionic polymers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6093391A (en) * 1992-10-08 2000-07-25 Supratek Pharma, Inc. Peptide copolymer compositions
US5846558A (en) * 1996-03-19 1998-12-08 Minnesota Mining And Manufacturing Company Ionically conductive adhesives prepared from zwitterionic materials and medical devices using such adhesives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7300990B2 (en) * 2000-10-06 2007-11-27 Biocompatibles Uk Limited Zwitterionic polymers
US20050123501A1 (en) * 2002-01-16 2005-06-09 Lewis Andrew L. Polymer conjugates
US20050163743A1 (en) * 2002-03-07 2005-07-28 Lewis Andrew L. Composition of polymers
US20060135714A1 (en) * 2003-01-16 2006-06-22 Lewis Andrew L Conjugation reactions
US20060069203A1 (en) * 2003-02-05 2006-03-30 Lewis Andrew L Block copolymers

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US9238065B2 (en) * 2000-12-19 2016-01-19 Zoetis Services Llc Mycoplasma hyopneumoniae bacterin vaccine
US20050123501A1 (en) * 2002-01-16 2005-06-09 Lewis Andrew L. Polymer conjugates
US8048408B2 (en) 2002-01-16 2011-11-01 Biocompatibles Uk Limited Polymer conjugates
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US8182802B2 (en) 2002-03-07 2012-05-22 Biocompatibles Uk Limited Composition of polymers
US20090036389A1 (en) * 2002-03-29 2009-02-05 Abbott Laboratories Polymeric Micelle Formulations of Hydrophobic Compounds and Methods
US20060135714A1 (en) * 2003-01-16 2006-06-22 Lewis Andrew L Conjugation reactions
US8053520B2 (en) 2003-01-16 2011-11-08 Biocompatibles Uk Limited Conjugation reactions
US8445612B2 (en) 2003-01-16 2013-05-21 Biocompatibles Uk Limited Conjugation reactions
US20060069203A1 (en) * 2003-02-05 2006-03-30 Lewis Andrew L Block copolymers
US7820753B2 (en) 2003-02-05 2010-10-26 Biocompatibles Uk Limited Block copolymers
US20050214379A1 (en) * 2004-01-02 2005-09-29 Sandro Mecozzi Encapsulation of chemical compounds in fluorous-core and fluorous-inner-shell micelles formed from semifluorinated-block or fluorinated-block copolymers
US8318204B2 (en) * 2005-03-18 2012-11-27 Sungkyunkwan University Foundation For Corporate Collaboration pH sensitive block copolymer and polymeric micelle using the same
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US8349991B2 (en) * 2005-04-19 2013-01-08 Massachusetts Institute Of Technology Amphiphilic polymers and methods of use thereof
US20060269479A1 (en) * 2005-04-19 2006-11-30 Colton Clark K Amphiphilic polymers and methods of use thereof
WO2007063320A1 (fr) * 2005-12-03 2007-06-07 The University Of Sheffield Gelificateur polymere
US9220689B2 (en) * 2006-09-06 2015-12-29 Dsm Ip Assets B.V. Nanoparticles
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US8846839B2 (en) 2006-11-21 2014-09-30 Abbott Laboratories Copolymers having zwitterionic moieties and dihdroxyphenyl moieties and medical devices coated with the copolymers
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