CN102112117A - Particle compositions with a pre-selected cell internalization mode - Google Patents
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- CN102112117A CN102112117A CN200880130677XA CN200880130677A CN102112117A CN 102112117 A CN102112117 A CN 102112117A CN 200880130677X A CN200880130677X A CN 200880130677XA CN 200880130677 A CN200880130677 A CN 200880130677A CN 102112117 A CN102112117 A CN 102112117A
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Abstract
A method of formulating a particle composition having a pre-selected cell internalization mode involves selecting a target cell having surface receptors and obtaining particles that have i) surface moieties, that have an affinity for or are capable of binding to the surface receptors of the cell and ii) a preselected shape, where a surface distribution of the surface moieties on the particles and the shape of the particles are effective for the pre-selected cell internalization mode.
Description
Statement about federal funding research
Obtain the support of the Federal funds of fund W81XWH-04-2-0035 of Ministry of National Defence and NASA fund SA23-06-017 as some researchs on basis of the present invention.U.S. government can enjoy some right of the present invention.
Technical field
The present invention relates in general to micron and Nanoparticulate compositions, and their application, more particularly, relates to micron and Nanoparticulate compositions with specific cells internalization pattern of selecting in advance.
Background technology
Endocytosis is definition cell input and/or exports the outer material of selected born of the same parents, as molecule, virus, granule and microorganism and with the general terms of the process of specific cells device in their targeting kytoplasms.Endocytosis can be carried out by all means, comprises endocytosis, the phagocytosis that clathrin mediation and caveola mediate, the endocytosis that does not rely on clathrin and caveola.Concrete endocytosis path can be depending on the size and the character of the outer material of born of the same parents, referring to for example Conner S.D. and S.L.Schmid.2003.Nature 422:37-44.For example, activating feature sizes is the caveola of 50-60nm, and promptly plasma membrane caves in and can assist the endocytosis of caveola mediation; The endocytosis of clathrin mediation needs the transmembrane receptor on the plasma membrane and the concentration of its binding partner to cause forming the vesicle cage (vesicular cage) that feature sizes is up to hundreds of microns (100-500nm); Phagocytosis comprises specific cells surface receptor and signal transduction cascade reaction, forms the cell membrane projection, finally wraps the exterior materials (＞1 μ m) of micron size.The endocytosis that does not rely on clathrin and caveola may be accompanied by the cave in vesicle of formation less than 100nm.
In some fields, for example in virusology, medicine and gene delivery and the nanometer toxicology field, the granule endocytosis may be extremely important, referring to for example Marsh M. and A.Helenius.2006.Cell124:729-40; Vasir J.K. and V.Labhasetwar.2006.Expert Opin.Drug Deliv.3:325-344; Oberdorster G., E.Oberdorster, J.Oberdorster.2005.113:823-39.
Granule with regard to the nanometer size, for example natural granule such as enveloped virus, or artificial granule such as bionical granule, the most effective internalization mechanism may be receptor-mediated endocytosis, the molecule (part) that wherein is distributed in particle surface combines with the antagonism molecule (receptor) of expressing on cell membrane, the final bending of the cell membrane parcel foreign substance that caves in is referring to for example Marsh M. and A.Helenius.2006.Cell 124:729-40; Smith A.E., A.Helenius.2004.Science 304:237-42.These receptors can be gathered in the site of caving in by diffusion into the surface, if do not have this effect then endocytosis can not take place, perhaps endocytosis needs the much longer time just can finish.
Summary of the invention
The method that embodiment provides a kind of preparation to have the particulate composition of the cell internalizing pattern of selecting in advance, this method comprises the cell of a) selecting to have surface receptor; And b) obtains granule, this granule has i) described receptor there is affinity or can be in conjunction with the surface portion of described receptor, ii) definite shape, the surface distributed of wherein said surface portion and described shape can make selected cell effectively realize the cell internalizing pattern of selecting in advance.
Another embodiment is the method for a kind of treatment or monitoring physiological condition, and described method comprises the particulate composition of the object effective dose that needs, and said composition has the cell internalizing pattern of selecting in advance.
Another embodiment is the particulate composition with cell internalizing pattern of selecting in advance.
Description of drawings
Fig. 1 is the particulate sketch map with oval cross section.Ligand molecular on this particle surface can interact with the acceptor molecule on the surface of cell membrane.
Fig. 2 shows the particulate evolution of described elliptical cylinder body, shows half parcel time 0.5 τ
wCompare x with packages length
Maximum/ R
1With the relation of length-width ratio Γ (scope is 0.9 to 4), R
2Be fixed on 50nm.
Fig. 3 is Γ
MinimumWith R
2Graph of a relation, Γ wherein
MinimumBe corresponding to the fixedly R that partly wraps up the time minima
2The Γ value.Fig. 3 also is Γ
MinimumHalf parcel time and R
2Graph of a relation.
Fig. 4 shows the particulate evolution of described elliptical cylinder body, shows half parcel time 0.5 τ
wCompare x with packages length
Maximum/ R
1With the relation of length-width ratio Γ (scope is 0.9 to 4), volume is fixed (R
s=50nm).
Detailed Description Of The Invention
Associated documents
Following research paper and patent document (including it in this paper in full by reference) can help understanding the present invention:
1) PCT publication number WO is open on October 25th, 2007/120248,2007;
2) PCT publication number WO is open on April 10th, 2008/041970,2008;
3) PCT publication number WO is open on February 21st, 2008/021908,2008;
4) U.S. Patent Application Publication No. is open on May 1st, 2008/0102030,2008;
5) U.S. Patent Application Publication No. 2003/0114366;
6) Application No. 12/034,259, on February 20th, 2008 submit applications;
7) Application No. 12/110,515, on April 28th, 2008 submit applications;
8) Tasciotti etc., Nature Nanotechnology, the 3rd volume, 151-158,2008;
9) Decuzzi and Ferrari, Biomaterials 28,2007,2915-2922;
10) Decuzzi and Ferrari, Biophysical Journal, 94,2008,3790-3797.
Definition
Except as otherwise noted, " one " or " a kind of " refer to one/kind or a plurality of/kind.
Except as otherwise noted, term " endocytosis " and " endocytosis " refer to receptor-mediated endocytosis and receptor-mediated endocytosis respectively.
" microgranule " refers to that full-size is 1 micron to 1000 microns, or 1 micron to 100 microns granule described in some embodiments.
" nano-particle " refers to that full-size is less than 1 micron granule.
" phagocytosis " refers to the phagocyte by specialization, comprises the granule of macrophage, mononuclear cell and neutrophil cell absorption big (the characteristic size is above 2 microns).Phagocytosis is included in and forms projection on the cell membrane, finally wraps foreign particle.
" receptor-mediated endocytosis " or RME phalangeal cell internalization granule, some part that distributing on the particle surface, for example part can combine with the antagonism part of expressing on cell membrane (receptor).RME comprises the cell membrane bending, causes cell membrane to wrap up described granule fully, the described granule of final cell internalization.Through the particulate characteristic size of RME internalization less than granule through the phagocytosis internalization.RME is not limited to phagocyte.
" biodegradable " refers to the material that can dissolve or degrade in Physiological Medium, or can be under physiological condition by the physiology enzyme and/or the biocompatible polymeric material of under electrochemical conditions, degrading.
Summary of the invention
The inventor recognizes the importance of grain shape in the receptor-mediated endocytosis.Therefore, the invention provides the method that a kind of preparation has in advance the particulate composition of the cell internalizing pattern of selecting, its can comprise select target cell and obtain to have surface portion on the surface, this surface portion to the surface receptor on target cell surface have affinity or can with the bonded granule of described surface receptor.Distribution and the described coating of particles cell internalizing pattern in advance selected that can effectively realize selected cell of described surface portion on particle surface.
The cell internalizing pattern of Xuan Zeing can be selected from " endocytosis " or " non-endocytosis " pattern in advance." endocytosis " refers to can be wrapped up fully by cell membrane and the pattern of final internalization through receptor-mediated endocytosis granule, and " non-endocytosis " refers to the pattern that granule can partly be wrapped up by cell membrane at the most
In some embodiments, the cell internalizing pattern of selecting in advance can be baffle endocytosis or part endocytosis." endocytosis baffles " refers to that granule is only partly wrapped up by cell membrane and can not be by the pattern of cell internalizing.
Granule with cell internalizing pattern of selecting in advance can be used for treatment and/or monitoring physiological condition.In this case, but alternative, mammal for example, influenced by certain physiological situation in the preferred human body and its cell surface on have certain target site of surface receptor, and giving the compositions of described object effective dose, described compositions comprises the granule that has the internalization pattern of selecting in advance with regard to the cell of described target site.Described physiological situation can be a disease for example, as cancer or inflammation.
Usually, selected cell can be the cell that has any kind of surface receptor on the surface.In many embodiments, selected cell can be a mammalian cell, for example people's cell.
Selected concrete internalization pattern can be depending on required granule and uses.For example,, granule need be delivered to intracellular material when containing, during as preparation or therapeutic agent, and can preferably endocytosis pattern.On the other hand, when described granule contains when not needing to be delivered to intracellular material, can preferred non-endocytosis or impaired endocytosis.An example of this situation can be as PCT publication number WO 2008/021908 described multistage delivery carrier, the first order granule of wherein said carrier (inside comprises second level granule) is used for discerning and adhere to the target site in the endothelium, and can be by the endotheliocyte internalization.After the adhesion, first order granule can discharge second level granule.
In many embodiments, selected cell can be a non-phagocytic cell, promptly can't carry out phagocytotic cell.Phagocyte, the example that promptly carries out phagocytotic cell comprises neutrophil cell, mononuclear cell and macrophage.
In some embodiments, selected cell can be an endotheliocyte, vascular endotheliocyte for example, and target site can be the vascular site, for example fills formula (coopted) vascular, vascular tone vascular or normalization vascular again.With regard to the cell that fills the formula vascular, described surface receptor can be angiogenin 2 receptors; With regard to the cell of angiogenic vascular, described surface receptor can be VEGF (VEGF), basic fibroblast growth factor or endothelial marker thing such as α
vβ
3Integrin; With regard to the cell of normalization vascular again, described surface receptor can be the scaffolding protein of cancer embryo dependency cell adhesion molecule 1 (CEACAM1), endothelin-B receptor (ET-B), vascular endothelial growth factor receptor inhibitors Ge Lawen (gravin)/AKAP12, protein kinase A and Protein kinase C.
The surface portion of particle surface can be with the receptor complementation on the selected cell surface, described surface portion, for example, to receptor on the selected surface of cell membrane have affinity or can antibody bonded with it, aptamers or part.In some embodiments, described surface portion can comprise that selected surface of cell membrane receptor is had specific part.In some embodiments, described surface portion can comprise the no specific part to selected surface of cell membrane receptor.In other embodiments, described surface portion can comprise specificity and non-specific part simultaneously.
Granule with internalization pattern of selecting in advance can be the part of compositions, and described compositions also can comprise the granule of the internalization pattern of not selecting in advance.The amounts of particles that has in advance an internalization pattern of selecting can account at least 10% or at least 25% or at least 50% or at least 75% or at least 90% of total number of particles in the compositions.
In many embodiments, described granule can be an aspherical particle.In some embodiments, described granule can be the granule with circular cross section.In some embodiments, described granule can be oval granule.In other embodiments, described granule can be the cylindrical particle that has oval cross section on the direction perpendicular to cylinder axis.
In some embodiments, described particulate maximum characteristic size, the particulate main axis length that for example has oval cross section, can less than 2 microns, less than 1 micron or less than 800nm, or be 5nm to 500nm, 5nm to 800nm, 5nm to 1 micron, 10nm to 1 micron, 10nm to 800nm, 10nm to 500nm, 20nm to 1 micron, 20nm to 800nm, 20nm to 500nm, 50nm to 1 micron, 50nm to 800nm or 50nm to 500nm.
Preferred described particulate maximum characteristic size is significantly less than the characteristic size of selected cell.Described particulate maximum characteristic size can be than little at least 3 times, little at least 5 times, little at least 10 times, little at least 20 times, little at least 30 times, little at least 50 times, little at least 100 times, little at least 200 times, little at least 300 times, little at least 500 times of the characteristic sizes of selected cell, little at least 100 times.The excursion of the characteristic size of selected cell can be about 5 microns to about 40 microns, or is about 10 microns to about 30 microns.
In some embodiments, the granule that obtains can be the granule with convex lower surface, its local curvature and described part, making as the local surfaces density of part can be through the effective internalization granule of receptor-mediated endocytosis, this expression is with regard to the local surfaces density of described part, and the κ of local curvature is less than the curvature κ of maximum endocytosis
MaxMaximum endocytosis curve can be depending on the particle surface on the each several part and selected surface of cell membrane the density of receptor on the area density of the binding energy between the receptor, the bending energy factor of selected cell membrane, described the above part of granule and selected cell membrane.The method of estimating maximum endocytosis curvature is hereinafter disclosed.
In some embodiments, the local surfaces density of the above part of convex surface can be greater than the area density of the above part of other parts of described particle surface, thereby makes the skewness of described surface portion on particle surface.
With regard to the granule with oval cross section, obtaining to have in advance, the granule of the cell internalizing pattern of selection can comprise the granule that obtains to have corresponding to the length-width ratio of institute's lectotype.
For example, Fig. 1 has shown the particulate oval cross section of elliptical cylinder body through ligands specific receptors bind and membrane interaction.The area density of part is m on the described particle surface
l, and the area density of receptor is m on the described surface of cell membrane
r
Described oval cross section can be used R
1And R
2Characterize, they are half length of the axle of ellipse.Oval length-width ratio may be defined as Γ=R
1/ R
2Described particulate cross-sectional area is A=π R
1R
2=π Γ R
2 2=π R
s 2, R wherein
sBe to have the long-pending particle radius of same cross-sectional with circular cross section with oval granule.
Particulate geometric features can be by many to parameter, for example R
1And R
2, Γ and R
1, Γ and R
2, Γ and R
sOr Γ and V limit fully, and wherein V is a particle volume.
In one case, by Γ and R
2When limiting described particulate geometric features, the form parameter of the internalization pattern that decision is selected in advance can be specific R
2Length-width ratio Γ.
If the particulate length-width ratio of specific minor axis half length is less than first marginal value Γ '=(R
2κ
Max)
-1/2, the granule that then has oval cross section may be " non-endocytosis " pattern, wherein κ
MaxBe maximum endocytosis curvature, it is defined as follows.
If specific minor axis half long particulate length-width ratio is not more than the second marginal value Γ "=R
2κ
Max, then described granule can be the endocytosis pattern that baffles.
If the particulate length-width ratio of specific minor axis half length is greater than the first marginal value Γ ' and less than the second marginal value Γ ", then described granule can be the endocytosis pattern.
Maximum endocytosis curvature κ
MaxMay be defined as with regard to the spheroidal particle that has the part identical on the surface or have the reverse minimum endocytosis radius that the circular cross section granule is calculated selected cytometer with aspherical particle.
Available following formula (1) minimum endocytosis radius of assessment and maximum endocytosis curvature:
In above-mentioned equation, C is with respect to k
BThe ligand-receptor binding energy of T, wherein k
BBe the Bo Ciman constant, T is the temperature (representing absolute temperature with Kelvin) of cell and target site.C depends on that concrete ligand-receptor is right.Specifically,
It is the equilibrium dissociation constant of interactional ligand-receptor on cell/granular boundary.
Can estimate to draw by following relation
K wherein
dIt is the identical right equilibrium dissociation constant (for example, can in solution, measure by experiment) of ligand-receptor; H is the thickness of restricted area, and the ligand-receptor site only limits to this zone.In many cases, h can approximate 10nm.
B is the bending energy factor of cell membrane, can for example pass through, and Hochmuth, R.M., J.Biomech., 33:15-22,2000 methods that described in detail are measured.
m
rBe the average surface density on the receptor,, can utilize method known to those skilled in the art to measure m when granule during not with cell interaction
rFor example, can use and Panes J. etc., Am.J.Physiol.1995; The complementary radiolabeled monoclonal antibody of cell-cell adhesion molecule 1 receptor that 269 (6Pt2): H1955-64 describe in detail is measured m in vivo
rPerhaps, can utilize with the complementary fluorescently-labeled monoclonal antibody of described receptor and measure m
rThis fluorescently-labeled monoclonal antibody can be a U.S. Patent number 4,520, the antibody of 110 described phycoerythrin labellings.
m
lBe part m
lLocal surfaces density, can change this parameter by the size of controlling particulate functionalisation of surfaces condition and/or changing ligand molecular.Can pass through radioactive test, utilize the real surface density of part on flow cytometry (citofluometry) or the radiolabeled antagonism molecule checking granule.
With regard to the granule that the surface ligand with homogeneous distributes, local surfaces density can be identical with average surface density.
In some embodiments, can assess minimum endocytosis radius and maximum endocytosis curvature by Application No. 12/034,259 " endocytosis granule (Endocytotic particles) " (including it in this paper in full by reference) described method of submitting to as on February 20th, 2008.
Fig. 2 shows the particulate evolution of described elliptical cylinder body, shows half parcel time 0.5 τ
wCompare x with packages length
Maximum/ R
1With the relation of length-width ratio Γ (scope is 0.9 to 4), through theoretical model evaluation (as by reference it being included in full in Decuzzi and the Ferrari of this paper, Biophysical Journal, 94,2008,3790-3797 is described), R
2=50nm.x
MaximumBe the projection of granule packages length on the x axle among Fig. 1.At x
Maximum/ R
1=1 o'clock, at τ
wParcel fully takes place in the place.In Fig. 2, Γ＜Γ '
CrThe time (being about 0.9 in this case), parcel can't begin, and causes τ
wInfinity, x
Maximum/ R
1Ratio is zero.For Γ '
Cr＜Γ＜Γ "
CrIn intermediate value Γ, ratio x
Maximum/ R
1Be always 1, mean that granule is by complete internalization, 0.5 τ
wAlong with almost being linear, the increase of Γ increases.Γ＜Γ "
CrThe time, x
Maximum/ R
1Reduce, reach minima, raise and raise steadily along with Γ then.
Fig. 3 is Γ
MinimumWith R
2Graph of a relation, Γ wherein
MinimumBe corresponding to the fixedly R that partly wraps up the time minima
2The Γ value.Fig. 3 also is Γ
MinimumHalf parcel time and R
2Graph of a relation.Phase same date and Γ '
CrAnd Γ "
CrList in table 1.
Table 1
R
2, nm Γ
Minimum(0.5 τ
w)
Minimum, second Γ '
CrΓ "
Cr
38.35 (=R
Water) 1 ∞ 11
50 0.96 41.60 0.87 1.30
75 0.80 78.33 0.71 1.95
100 0.68 123.4 0.62 2.61
150 0.56 243.7 0.50 3.91
300 0.40 823.6 0.36 7.82
500 0.32 2105.2 0.28 13.0
Along with granularity R
2Rising, length-width ratio Γ
Minimum(internalization time minimum) is from 1 (R
2=R
Minimum) be reduced to 0.3 (R
2=500nm).
In some cases, two parameters of the particulate geometric features of description elliptical cylinder body can be Γ and R
s
In this case, determine that the form parameter of the cell internalizing pattern of selection can be specific R in advance
sThe length-width ratio Γ of value.
If the particulate length-width ratio of specific minor axis half length is less than the first marginal value Γ
1'=(R
sκ
Max)
-2/3, the granule that then has oval cross section can be " non-endocytosis " pattern, wherein κ
MaxBe maximum endocytosis curvature, it is defined as follows.
If specific minor axis half long particulate length-width ratio is not more than the second marginal value Γ
1"=(R
sκ
Max)
2/3, then described granule can be the endocytosis pattern that baffles.
If the particulate length-width ratio of specific minor axis half length is greater than the first marginal value Γ
1' and less than the second marginal value Γ
1", then described granule can be the endocytosis pattern.
Fig. 4 shows the particulate evolution of described elliptical cylinder body, shows half parcel time 0.5 τ
wCompare x with packages length
Maximum/ R
1With the relation of length-width ratio Γ (scope is 0.9 to 4), through theoretical model evaluation (as by reference it being included in full in Decuzzi and the Ferrari of this paper, Biophysical Journal, 94,2008,3790-3797 is described), R
s=50nm.
Grain type
Specifically do not limit grain type with internalization pattern of selecting in advance.For example, described granule can be liposome, polymer-matrix granule, silica-based and silica-based particles, quantum dot, nanometer gold shell, dendrimer (dendrimer) or virion.
In some embodiments, can make granule with the shape that can effectively realize selecting in advance the internalization pattern.In other embodiments, it is optional from shape and/or size distribution granule storehouse widely to have a granule of the shape that can effectively realize selecting in advance the internalization pattern.Can utilize (for example) Zetasizer from the Ma Erwen instrument company (Malvern Instruments, Worcestershire, United Kingdom) of Britain Worcestershire
TMThe nano series instrument is selected from described granule storehouse, and this instrument can be measured particulate physical dimension.
Can utilize several different methods to make granule.Usually, can preferably can control the manufacture method of particulate size and shape.
In some embodiments, can pass through top-down micron manufacture method or nanometer manufacture method, granule as described in making as lithoprinting, electron beam lithography, X ray lithographic printing, dark UV lithographic printing or nanometer lithographic printing.Using the advantage of top-down manufacture method may be that these class methods can be used for the granule of large-scale production size homogeneous.
Can have targeting moiety on these particulate surfaces, as part, aptamers or antibody.For example, can part be connected in reactive group suitable on the particle surface by chemical mode.Can effectively form under the condition of thioether and amido link, protein ligands is being connected in amino-and sulfydryl-reactive group.The method that connects antibody or other polymeric binders on inorganic or polymerization holder can be referring to (for example) Taylor, R. compile, " protein is principle and application fixedly " (Protein Immobilization Fundamentals and Applications), the 109110th page (1991).
For example, when preparing granule, can realize the heterogeneity surface distributed of surface portion with top-down micron manufacturing or nanometer manufacture method.For example, can utilize opposing part sedimentary coating to make and make particulate base material patternsization, so that this granule has at least two kinds of different surf zones: a kind ofly can resist the part deposition and another kind can not.When base material contacts the solution that contains part subsequently, can produce the granule of part skewness one behind the base material release part.
In some embodiments, described granule can have the one or more passages that connect bank and surface.In some embodiments, described bank and passage can be the holes in the granule body.In this case, described granule can comprise porous or nanoporous material.The hole of may command porous or nanoporous material is with activating agent and/or the required rate of release that reaches required loading.Nanoporous material with control pore size can be an oxide material, as SiO
2, Al
2O
3Or TiO
2The nanoporous oxide particle, be also referred to as the particulate manufacturing of collosol and gel can referring to, for example, Paik J.A. etc., J.Mater.Res., the 17th the volume, in August, 2002.Nanoporous material with control pore size also can be a nanoporous silicon.The manufacturing of nanoporous silicon grain can referring to, Cohen M.H. etc. for example, Biomedical Microdevices 5:3,253-259,2003.
In some other embodiments, described granule may be fully without any passage.This class granule can comprise, for example, and biodegradable material.For example, described granule can be made of metal (as ferrum, peptide, gold, silver, platinum, copper), alloy and its oxide.Described biodegradable material also can be a Biodegradable polymeric, as poe, polyanhydride, polyamide, polyalkyl alpha-cyanacrylate, polyphosphazene and polyester.Exemplary Biodegradable polymeric is referring to for example, United States Patent (USP) 4,933,185,4,888,176 and 5,010,167.The object lesson of this Biodegradable polymeric material comprises poly-(lactic acid), polyglycolic acid, polycaprolactone, poly butyric ester, poly-(N-palmityl-trans-4-hydroxy-l-proline ester) and poly-(DTH carbonic ester).
In some embodiments, described granule itself just can be an activating agent.
Activating agent
Activating agent can be therapeutic compound and/or preparation.Required application is depended in the selection of aggressiveness activating agent.
Therapeutic agent can be can be at object, as producing the physiology or the pharmacological active substance of required biological action in mammal or people's the porose vascular.Therapeutic agent can be inorganic or organic compound, comprises peptide, protein, nucleic acid and micromolecule.Therapeutic agent can adopt various forms, uncharged molecule for example, molecular complex, the acceptable salt example hydrochloric acid of pharmacology salt, hydrobromate, sulfate, laruate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, Salicylate etc.For acid therapeutic agent, can adopt slaine, amine salt or organic cation salt, for example quaternary ammonium salt.Medicaments derivative is as alkali, ester and amide also useful as therapeutics.Water-fast therapeutic agent can its soluble derivative or the form of alkali derivant use, under any therein situation or by sending, these derivants can transform by the effect of enzyme, transform by health pH hydrolysis or by other metabolic process, form initial therapeutic activity form.
Therapeutic agent can be to can be natural generation or pass through prodrug synthetic or chemotherapeutics, immunosuppressant, cytokine, cytotoxic agent, molten nuclear compound, radiosiotope, receptor and kinase that recombination method produces, or their any combination.
Lock into the medicine of classical multidrug resistance effect, as vinca alkaloids (as vinblastine and vincristine), anthracycline antibiotics (as doxorubicin and daunomycin), rna transcription inhibitor (as actinomycin D) and microtubule stablize medicine (as paclitaxel) may be especially suitable for use as described in therapeutic agent.
Cancer chemotherapeutic agent also can be preferred therapeutic agent.Useful cancer chemotherapy medicated bag is drawn together chlormethine, nitroso ureas, aziridine, alkylsulfonate, tetrazine, platinum compounds, pyrimidine analogue, purine analogue, antimetabolite, folacin, anthracycline antibiotics, taxane, vinca alkaloids, topoisomerase enzyme inhibitor and hormone drug.Exemplary chemotherapeutic is an actinomycin D, L-Sarcolysinum (Alkeran), Ara-C, Anastrozole, asparaginase, BiCNU, bicalutamide, bleomycin, busulfan, capecitabine, carboplatin, carboplatin, carmustine, CCNU, chlorambucil, cisplatin, cladribine, CPT-11, cyclophosphamide, cytosine arabinoside, the cytosine cytosine arabinoside, cyclophosphamide, dacarbazine, the D D actinomycin D, daunomycin, dexrazoxane, docetaxel, doxorubicin, DTIC, epirubicin, aziridine, etoposide, floxuridine, fludarabine, fluorouracil, flutamide, fotemustine, gemcitabine, He Saiting, hexamethylamine, hydroxyurea, the jaundice element, ifosfamide, irinotecan, lomustine, chlormethine, melphalan, purinethol, methotrexate, mitomycin, mitotane, mitoxantrone, oxaliplatin, paclitaxel, pamidronic acid, pentostatin, plicamycin, procarbazine, Rituximab, steroid, streptozocin, STI-571, streptozocin, tamoxifen, the temozolomide, teniposide, tetrazine, thioguanine, thiotepa, Tomudex (Tomudex), topotecan, treosulfan (Treosulphan), trimetrexate, vinblastine, vincristine, vindesine, vinorelbine, VP-16 and Xeloda.
Useful cancer chemotherapy medicine also comprises alkylating agent, as thiotepa and cyclophosphamide; Alkylsulfonate is as busulfan, an improsulfan and piposulfan; Ethylene imine is as benzodepa, carboquone, meturedepa and uredepa; Aziridine and first melamine comprise altretamine, tretamine, triethylenephosphoramide, triethylene thiophosphoramide and trimethylolmelamine; Chlormethine is as chlorambucil, chlornaphazine, chlorine phosphamide, estramustine, ifosfamide, chlormethine, mustron, melphalan, promise Fan Biying (Novembiehin), NSC-104469, prednimustine, trofosfamide, uracil mustard; Nitrourea is as carmustine (Cannustine), chlorozotocin, fotemustine, lomustine, nimustine and Ranimustine; Antibiotic is as aclarubicin, D actinomycin D, antramycin, azaserine, bleomycin, the C D actinomycin D, calicheamicin, OK a karaoke club is than star (Carabicin), carminomycin, cardinophyllin, chromomycin, the D D actinomycin D, daunomycin, detorubicin, 6-diazonium-5-oxo-L-nor-leucine, doxorubicin, epirubicin, esorubicin, idarubicin (idambicin), the Marcelo mycin, mitomycin, mycophenolic acid, nogalamycin, Olivomycin, peplomycin, Bo Feiluo mycin (potfiromycin), puromycin, triferricdoxorubicin, rodorubicin, rufocromomycin, streptozocin, tubercidin, ubenimex, zinostatin and zorubicin; Antimetabolite such as methotrexate and 5-fluorouracil (5-FU); Folacin is as 9,10-dimethylpteroylglutamic acid, methotrexate, Pteropterin and trimetrexate; Purine analogue is as fludarabine, Ismipur, ITG and thioguanine; Pyrimidine analogue, as ancitabine, azacitidine, 6-azauridine, carmofur, cytosine arabinoside, two BrdU, doxifluridine, enocitabine, floxuridine and 5-FU; Androgen is as calusterone, dromostanolone propionate, epitiostanol, mepitiostane (Rnepitiostane) and Testolactone; Antiadrenergic agent is as aminoglutethimide, mitotane and trilostane; Folic acid supplement such as leaf alkanoic acid; Aceglatone; The aldophosphamide glycosides; Amino-laevulic acid; Amsacrine; Shellfish granny rag former times (Bestrabucil); Bisantrene; Yi Da Qu Sha; Defosfamide (defofamine); Demecolcine; Diaziquone; Ai Funixin (Elfornithine); According to sharp vinegar amine; Etoglucid; Ganite (Fujisawa).; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; C-283; Pentostatin; Phenamet; Pirarubicin; Podophyllinic acid; 2-ethyl hydrazides; Procarbazine;
Razoxane; Sizofiran (Sizofran); Spirogermanium; Tenuazonic acid; Triaziquone; 2,2 ', 2 "-RA3; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Add cytosine; Cytosine arabinoside (" Ara-C "); Cyclophosphamide; Thiotepa; Taxanes is as paclitaxel (taxol
This Shi Guibao company of the Bristol-mayer of Princeton, New Jersey (Bristol-Myers Squibb Oncology, Princeton, NJ)) and docetaxel (taxotere
The RPR company in Anthony, France city (Rhone-Poulenc Rorer, Antony, France)); Chlorambucil; Gemcitabine; The 6-thioguanine; Purinethol; Methotrexate; Platinum analogs is as cisplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Ametycin; Mitoxantrone; Vincristine; Vinorelbine; Nvelbine; Dihydroxyanthraquinone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase enzyme inhibitor RFS 2000; Er Fujiajiniaoansuan (DMFO); Tretinoin; The Ai Sipeila mycin; Capecitabine; Pharmaceutically acceptable salt, acid or derivant with said medicine.The present invention also comprise be used to regulate or inhibitory hormone to the antihormone agent of the effect of tumor, as the estrogen antagonist agent, comprise for example tamoxifen, raloxifene, aromatase inhibition 4 (5)-imidazoles, 4 trans-Hydroxytamoxifens, trioxifene, triumphant former times sweet smell (Keoxifene) difficult to understand, onapristone and toremifene (Fareston); With the androgen antagonist agent, for example flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; And the pharmaceutically acceptable salt of said medicine, acid or derivant.
Cytokine is useful as therapeutics also.The example of this type cytokines is lymphokine, monokine and traditional polypeptide hormone.Cytokine comprises growth hormone, as human growth hormone, N-methionyl human growth hormone and bovine growth hormone; Parathyroid hormone; Thyroxine; Insulin; Proinsulin; Relaxin; Relaxation precipitinogen; Glycoprotein hormones is as follicle stimulating hormone (FSH), thyrotropin (TSH) and lutropin (LH); Liver growth factor; Fibroblast growth factor; Prolactin antagonist; Galactagogin; Tumor necrosis factor-alpha and-β; MIS; Mice gonadotropin related peptides; Inhibin; Activin; VEGF; Integrin; Thrombopoietin (TPO); Nerve growth factor is as NGF-β; PDGF; Transforming growth factor (TGF) is as TGF-α and TGF-β; Insulin like growth factor-1 and-II; Erythropoietin (EPO); Bone-inducing factor; Interferon such as interferon-' alpha ' ,-β and-γ; Colony stimulating factor (CSF) is as macrophage-CSF (M-CSF); Granulocyte-macrophage-CSF (GM-CSF); And granulocyte-CSF (GCSF); Interleukin (IL) is as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15; Tumor necrosis factor is as TNF-α or TNF-β; With other polypeptide factor, comprise LIF and kit part (KL).Term " cytokine " used herein " comprise the protein that natural origin or reconstitution cell culture are originated, and the biological activity equivalent of native sequences cytokine.
Preparation can be can provide in the relevant animal body, as the material of the image-forming information of mammal or the intravital target site of people.Preparation can comprise magnetic material, and for example ferrum oxide is used for nuclear magnetic resonance.In optical imagery, activating agent can be, for example, and semiconductor nanocrystal or quantum dot.In the optical coherence fault imaging, preparation can be metal (for example gold or silver) nanocages granule.Preparation also can be an acoustic contrast agent, for example micron or nanometer bubble, perhaps ferrum oxide micron or nano-particle.
Compositions
The granule that has the internalization pattern of selecting in advance with regard to particular cell types can be made compositions, for example part of pharmaceutical compositions.This compositions can be to be used to give comprising of therapeutic agent or preparation above-mentioned particulate suspension.For forming suspension, described granule can selected concentration be suspended in the aqueous medium.Optimal concentration can be depending on particle characteristic (as dissolution characteristics), treatment application type and mode of administration.For example, being used for liquid preparations for oral administration can be dense relatively thick, thereby can contain the granule of higher concentration (as＞50%).The solution that is used to inject preferably contains spissated relatively particle suspension liquid (as 10-50%), but its concentrating degree can only make its viscosity a little more than saline (so that at utmost reducing the use of macropore syringe needle).Because the liquid larger volume that gives, the solution that is used for continuous intravenous infusion contains the granule of low concentration (as the 2-10% suspension) usually.
Granule can be suspended in the multiple suitable aqueous carrier.Suitable pharmaceutical carrier can be under used dosage and concentration to the receiver nontoxic and with preparation in the compatible carrier of other composition.The example of suitable carriers includes but not limited to water, saline, Ringer's solution, dextrose solution and 5% human serum albumin.The suspension that is used for ejection preparation preferably oozes with object blood etc.Usually, described carrier can contain a small amount of additive, as strengthen the material of isotonicity and chemical stability, as buffer agent and antiseptic, and polypeptide, protein, the aminoacid of low-molecular-weight (less than about 10 residues), steamed bun stuffed with sugar is drawn together glucose or dextran, chelating agen such as EDTA, or other excipient.
Before giving object, can sterilize to particle suspension liquid by the suitable sterile method.The granule of being made by the heat stability material can carry out heat sterilization, for example uses the autoclave sterilization.Can sterilize by commercially available sterilization filter with the granule that non-heat stability material is made.Certainly, could use filtration sterilization at granule during less than the aperture of sterilization filter.
The object that can granule be needed the treatment intervention by suitable medication.The ad hoc approach that is used for application-specific can be determined by the doctor in charge.For example, described granule can be by a kind of the giving in the following approach: local, gastrointestinal tract is outer, suction, oral, vagina and anus approach.Can give in the preferred especially blood vessel, comprise intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection.
Give in the blood vessel to adopt part or systemic fashion.By the guide catheter system, cat scan guide catheter is for example sent in the local vascular and be can be used for described particle delivery near the known body part that tumor or inflammation arranged.Normal injection, as inject, i.v. injection or continuously/drop i.v. infusion general normally.
Described granule can be expelled in the blood flow, and make its circulation and be positioned to its target site.Preferably granule is expelled in the blood vessel of target site.
List of references
1.Gao H. etc., 2005.Proc.Natl.Acad.Sci.USA 102:9469-74.
2.Sun S.X. and D.Wirtz.2006.Biophysical Journal 90:L10-2.
3.Champion J.A. etc., 2007.Proc.Natl.Acad.Sci.USA 104:11901-4.
4.Champion?J.A.，S.Mitragotri.2006.Proc.Natl.Acad.Sci.USA103：4930-4.
5.Rolland J.P. etc., 2005.J.Am.Chem.Soc.127:10096-100.
6.Cohen M.H. etc., 2001.Biomedical Microdevices 3:253-259.
7.Harris A, G. etc., 2006.Proc.Natl.Acad.Sci.USA 103:19123-7
8.Freund L.B. and Y.Lin.2004.Journal of the Mechanics and Physics of Solids 52:2455-2472
9.Hill TL.1960. " statistics thermokinetics introduction " (An Introduction to Statistical Thermodynamics). New York Dove publishing company (Dover Publications, Inc.New York).
10.Herant M. etc., 2006.J.Cell.Sci.119:1903-13.
11.Smythe?E.，K.R.Ayscough.2006.J.Cell?Sci.119：4589-98.
12.May?R.C.，L.M.Machesky.2001.J.Cell?Sci.114：1061-77.
13.Simson R. etc., 1998.Biophysical Journal.74:514-522.
14.Herant M. etc., 2005.J.Cell Sci.118:1789-97.
***
Though above mention the specific embodiment, should understand the present invention and not be limited.Those of ordinary skills should be understood that and can carry out various changes to disclosed embodiment that these changes should fall into the scope of the invention.
All publications, patent application and the patent that this paper quotes included this paper all by reference in full in.
Claims (22)
1. a preparation has the method for the particulate composition of the cell internalizing pattern of selecting in advance, and described method comprises:
A) selection has the cell of surface receptor; With
B) obtain granule, this granule has i) described receptor there is affinity or can be in conjunction with the surface portion of described receptor, ii) definite shape, the surface distributed of wherein said surface portion and described shape can make selected cell effectively realize the cell internalizing pattern of selecting in advance.
2. the method for claim 1 is characterized in that, the described internalization pattern of selecting in advance is selected from complete endocytosis, endocytosis or non-endocytosis baffle.
3. the method for claim 1 is characterized in that, described cell is an endotheliocyte.
4. method as claimed in claim 3 is characterized in that, described endotheliocyte is the vascular endotheliocyte.
5. method as claimed in claim 4 is characterized in that, described receptor is angiogenesis vascular receptor, fill formula vascular receptor or normalization receptor again.
6. the method for claim 1 is characterized in that, described cell is a non-phagocytic cell.
7. the method for claim 1 is characterized in that, described surface portion is can be in conjunction with the part of described receptor.
8. the method for claim 1 is characterized in that, described acquisition comprises makes described granule.
9. method as claimed in claim 8 is characterized in that, described manufacturing comprises by top-down method manufacturing.
10. method as claimed in claim 8 is characterized in that, described manufacturing comprises described part is placed on the described particulate surface.
11. the method for claim 1 is characterized in that, described acquisition comprises selects described granule from particle swarm.
12. the method for claim 1 is characterized in that, described granule comprises activating agent.
13. method as claimed in claim 12 is characterized in that, described activating agent comprises preparation or therapeutic agent.
14. the method for claim 1 is characterized in that, described granule is a nano-particle.
15. the method for claim 1 is characterized in that, described granule is an aspherical particle.
16. the method for claim 1 is characterized in that, described granule is the granule with circular cross section.
17. the method for claim 1 is characterized in that, described granule is oval granule.
18. method as claimed in claim 17 is characterized in that, the particulate length and width specific energy of described ellipse makes selected cell effectively realize the cell internalizing pattern of selecting in advance.
19. method as claimed in claim 18 is characterized in that, also comprises according to the area density of described surface portion and the area density of described surface receptor determining described length-width ratio.
20. the method for claim 1 is characterized in that, described particulate surface comprises convex surface, and the local surfaces density of its curvature and described part can effectively realize the endocytosis pattern selected in advance.
21. the treatment or the method for monitoring physiological condition, described method comprises the particulate composition of the object effective dose that needs, and said composition method according to claim 12 is prepared.
22. one kind according to the described method composition prepared of claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2008/071470 WO2010014081A1 (en) | 2008-07-29 | 2008-07-29 | Particle compositions with a pre-selected cell internalization mode |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102112117A true CN102112117A (en) | 2011-06-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880130677XA Pending CN102112117A (en) | 2008-07-29 | 2008-07-29 | Particle compositions with a pre-selected cell internalization mode |
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| Country | Link |
|---|---|
| EP (1) | EP2326314A1 (en) |
| JP (1) | JP2011529491A (en) |
| KR (1) | KR20110039466A (en) |
| CN (1) | CN102112117A (en) |
| AU (1) | AU2008360004A1 (en) |
| CA (1) | CA2732252A1 (en) |
| MX (1) | MX2011001121A (en) |
| WO (1) | WO2010014081A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170000875A1 (en) | 2013-12-02 | 2017-01-05 | Arytha Biosciences, Llc | Toxoid preparation and uses thereof |
| WO2015187502A1 (en) | 2014-06-02 | 2015-12-10 | Cellics Therapeutics, Inc. | Use of nanoparticles coated with red blood cell membranes to treat hemolytic diseases and disorders |
| WO2016109306A1 (en) | 2015-01-02 | 2016-07-07 | Cellics Therapeutics, Inc. | Use of nanoparticles coated with red blood cell membranes to enable blood transfusion |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008021908A2 (en) * | 2006-08-08 | 2008-02-21 | Board Of Regents Of The University Of Texas | Multistage delivery of active agents |
| US8563022B2 (en) * | 2006-10-11 | 2013-10-22 | Board Of Regents Of The University Of Texas System | Particles for cell targeting |
-
2008
- 2008-07-29 CN CN200880130677XA patent/CN102112117A/en active Pending
- 2008-07-29 KR KR1020117003851A patent/KR20110039466A/en not_active Application Discontinuation
- 2008-07-29 EP EP08782489A patent/EP2326314A1/en not_active Withdrawn
- 2008-07-29 MX MX2011001121A patent/MX2011001121A/en not_active Application Discontinuation
- 2008-07-29 WO PCT/US2008/071470 patent/WO2010014081A1/en active Application Filing
- 2008-07-29 CA CA2732252A patent/CA2732252A1/en not_active Abandoned
- 2008-07-29 JP JP2011521073A patent/JP2011529491A/en active Pending
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Also Published As
| Publication number | Publication date |
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| CA2732252A1 (en) | 2010-02-04 |
| EP2326314A1 (en) | 2011-06-01 |
| MX2011001121A (en) | 2011-05-23 |
| WO2010014081A1 (en) | 2010-02-04 |
| KR20110039466A (en) | 2011-04-18 |
| JP2011529491A (en) | 2011-12-08 |
| AU2008360004A1 (en) | 2010-02-04 |
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