WO2021145543A1 - Conjugué constitué d'une matrice extracellulaire et d'un médicament anticancéreux, et son utilisation médicale - Google Patents

Conjugué constitué d'une matrice extracellulaire et d'un médicament anticancéreux, et son utilisation médicale Download PDF

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WO2021145543A1
WO2021145543A1 PCT/KR2020/015525 KR2020015525W WO2021145543A1 WO 2021145543 A1 WO2021145543 A1 WO 2021145543A1 KR 2020015525 W KR2020015525 W KR 2020015525W WO 2021145543 A1 WO2021145543 A1 WO 2021145543A1
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rep
conjugate
extracellular matrix
doxorubicin
cancer
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Korean (ko)
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전원배
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재단법인 대구경북과학기술원
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Priority to JP2022537781A priority Critical patent/JP7387899B2/ja
Publication of WO2021145543A1 publication Critical patent/WO2021145543A1/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an extracellular matrix composed of an elastin-like polypeptide and an integrin receptor ligand and an anticancer drug conjugate, and to a medical use thereof.
  • Cancer is a disease in which cells do not differentiate normally due to an abnormality in the cell cycle constituting human tissue and continue to divide. Cancer occurs through three stages: initiation, promotion, and progression. . It is known that cancer is caused by mutations in genes or cancer suppressor genes in normal cells by carcinogens contained in the environment or food, and these cells proliferate abnormally and form cancerous tissues while receiving continuous stimulation from carcinogens. The cause of cancer has not yet been clearly elucidated.
  • Cancer is divided into benign tumors and malignant tumors.
  • Benign tumors have a relatively slow growth rate and metastasis, which moves from the original site of the tumor to other tissues, whereas malignant tumors do not appear. Tumors leave the primary part and infiltrate other tissues and rapidly grow, which is life-threatening and is a very important cause of death.
  • Surgical therapy, radiation therapy, chemotherapy, etc. are used for the treatment of these cancers, but it is reported that more than 50% of all cancer patients eventually die without being cured despite many studies.
  • the reason for this is that even after surgical resection, the cancer recurs because the microscopically metastasized cancer cells cannot be removed, or when cancer treatment using an anticancer agent is used despite the development of various anticancer agents, the cancer cell death is not induced or the cancer cell death is not induced by the anticancer agent at the initial stage This is because the tumor appears to be shrinking because it responds to anticancer drugs, but cancer cells that have developed resistance to anticancer drugs rapidly proliferate during or after treatment.
  • Chemotherapy a low-molecular-weight chemotherapy, has been widely used for the treatment of various types of cancer, but the clinical efficacy of chemotherapy is limited due to the non-specificity of anticancer drugs that cannot distinguish the difference between cancer cells and normal cells.
  • anticancer drugs for the clinical effect of anticancer drugs, it is administered at the maximum tolerated amount that induces side effects.
  • One of the long-term side effects of chemotherapy is multidrug resistance, and it is known that P-glycoprotein pumps anticancer agents in cancer cells to induce multidrug resistance. there is.
  • the present invention provides a conjugate consisting of an extracellular matrix consisting of an elastin-like polypeptide and an integrin receptor ligand and an anticancer agent in order to greatly increase the accessibility of an anticancer agent to tumor tissue, minimize side effects on normal tissues, and improve the anticancer therapeutic effect on cancer cells. It is intended to provide a pharmaceutical composition for anticancer treatment or a pharmaceutical composition for inhibiting drug resistance.
  • the present invention relates to a conjugate consisting of an extracellular matrix (REP) and an anticancer agent,
  • the extracellular matrix consists of an elastin-like polypeptide and an integrin receptor ligand,
  • the extracellular matrix and the anticancer agent provide an extracellular matrix and an anticancer agent conjugate for anticancer treatment, characterized in that they are connected to each other by a linker.
  • the present invention provides a pharmaceutical composition for treating cancer diseases containing the extracellular matrix and the anticancer drug conjugate as active ingredients.
  • the present invention provides a pharmaceutical composition for inhibiting drug resistance containing the extracellular matrix and the anticancer drug conjugate as active ingredients.
  • an extracellular matrix (REP)-doxorubicin conjugate comprising an elastin-like polypeptide and an integrin receptor ligand exhibited significantly improved anticancer activity compared to doxorubicin or a mixture of REP and doxorubicin, and drug resistance of cancer cells exhibiting doxorubicin resistance
  • the extracellular matrix (REP)-doxorubicin conjugate can be provided as an effective anticancer agent for the treatment of cancer diseases and a pharmaceutical composition for inhibiting drug resistance of cancer cells exhibiting drug resistance to anticancer agents.
  • FIG. 1 is a schematic diagram illustrating the non-specific internalization between a drug and a receptor of a REP-drug conjugate. Since the REP-drug conjugate is not pumped out of cancer cells, multi-drug resistance can be avoided.
  • 3 is an amino acid sequence of a REP protein.
  • REP-doxorubicin is cytoplasmic (yellow arrow), nuclear (green arrow) and cytoplasmic It is the result of confirming that it is internalized in both the nucleus (blue arrow).
  • FIG. 14 is a result of comparing the cytotoxicity of doxorubicin, REP and doxorubicin mixture and REP-doxorubicin conjugate in PANC-1 cells.
  • the anticancer effect of doxorubicin was increased by 4 times during REP combination treatment, whereas REP-doxorubicin conjugate was compared with doxorubicin. This is the result of confirming that the anticancer activity was more than 20 times higher.
  • the present invention is an extracellular matrix protein-drug conjugate that is efficiently internalized into cancer cells through integrin receptor ligands on the cell surface to induce apoptosis of cancer cells, and consists of a heat-reactive peptide sequence to overcome P-glycoprotein-mediated multidrug resistance of cancer cells By confirming the present invention was completed.
  • the present invention relates to an extracellular matrix (RGD-containing Elastin-Like Polypeptide, REP) and a conjugate consisting of an anticancer agent,
  • the extracellular matrix is a polypeptide consisting of an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer agent are linked to each other by a linker. It can provide an extracellular matrix for anticancer treatment and an anticancer drug conjugate. .
  • VVPG valine-glycine-valine-proline-glycine
  • RGD arginine-glycine - aspartate
  • the extracellular matrix is composed of [VGRGD(VGVPG) 6 ] n , which is the amino acid sequence represented by SEQ ID NO: 3, wherein n is the number of repetitions of SEQ ID NO: 3 and an integer of 5 to 20. It may be a therapeutic extracellular matrix and an anticancer drug conjugate.
  • the extracellular matrix is composed of TGPG[VGRGD(VGVPG) 6 ] n WPC, which is the amino acid sequence shown in SEQ ID NO: 2, wherein n is [VGRGD(VGVPG) 6 ] 5, 10, It may be an integer of 12, 15 or 20.
  • the linker may be a C2 to C5 compound having two or more functional groups different from the group consisting of OH-, NH 2 - and SH-.
  • the linker may be selected from the group consisting of 3-sulfonylpropanehydrazide and 3-Mercaptopropionic acid.
  • the conjugate may be one in which the extracellular matrix and the SH- functional group of the linker are bonded, and the anticancer agent and the OH- or NH 2 - functional group of the linker are bonded to form the conjugate.
  • the anticancer agent is paclitaxel, doxorubicin, cis-platin, dodetaxel, tamoxifen, camptothecin, anasterozole, carboplatin ), topotecan, berotecan, irinotecan, gleevec, monomethyl auristatin E (MMAE), mertansine (DM1), sorabtansine (DM4) and vincristine ) may be selected from the group consisting of.
  • MMAE monomethyl auristatin E
  • DM1 mertansine
  • DM4 sorabtansine
  • vincristine vincristine
  • the present invention can provide a pharmaceutical composition for treating cancer diseases containing the extracellular matrix and the anticancer drug conjugate as active ingredients.
  • the cancer disease may be selected from the group consisting of liver cancer, kidney cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, brain cancer, stomach cancer, ovarian cancer and uterine cancer.
  • the pharmaceutical composition may increase apoptosis of tumor cells and inhibit anticancer drug resistance.
  • the present invention can provide a pharmaceutical composition for inhibiting drug resistance containing the extracellular matrix and the anticancer drug conjugate as active ingredients.
  • the drug resistance may be anticancer drug resistance of tumor cells.
  • the pharmaceutical composition is any one selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or liquids according to a conventional method. of the formulation can be used.
  • the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, flavoring agent, antioxidant, buffer, bacteriostatic agent, diluent commonly used in the preparation of pharmaceutical compositions.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules.
  • Such a solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition.
  • excipients for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition.
  • lubricants such as magnesium stearate and talc can also be used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base material for the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the pharmaceutical composition is administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject.
  • Preferred dosages of the extracellular matrix and the anticancer drug conjugate may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art.
  • the daily dose may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg.
  • Administration may be administered once a day or may be administered in several divided doses, thereby not limiting the scope of the present invention.
  • the 'subject' may be a mammal including a human, but is not limited to these examples.
  • the oligonucleotide for the unit gene (5'-aattcatatgggccacggcgtgggtcgtggcgatgtaggtgtcccaggtgtgggcgtaccgggcgttggtgttcctggtgtcggtgtcggtgtgccgggcgtaggtgtcccaggtgtgggcgccgggctggca-3') was chemically synthesized and inserted into the EcoRI and HidIII sites of the vector. To generate the REP gene, oligomerization of the unit gene was performed in a recursive directional ligation (RDL) method.
  • RTL recursive directional ligation
  • a novel expression vector pET-25b(+)-1 was created by ligating the oligonucleotide (5'-tatgaccgggccgggctggccgtgctgata-3') with the linear pET-25b(+).
  • the REP gene was cloned into pET-25b(+)-1 plasmid vector and transformed into E. coli BLR(DE3) by heat shock method.
  • Transformed E. coli cells stored at -80°C were inoculated into a starter culture medium (250 mL flasks containing 50 mL of medium supplemented with 100 ⁇ g/mL ampicillin) and cultured at 37°C overnight with stirring.
  • the starter culture was centrifuged at 3,000 g at 4° C. for 15 minutes and resuspended in 10 mL of fresh medium.
  • 5 mL of a starter culture solution suspended in an expression culture medium (4 L flasks containing 1 L of medium with 100 ⁇ g/mL ampicillin) was inoculated and cultured by stirring at 37°C.
  • IPTG final concentration of 1 mM
  • E. coli cells were resuspended in 35 mL of cold PBS buffer (pH 7.4) and sonicated at 4°C.
  • the cell lysate was centrifuged at 15,000 g at 4° C. for 15 minutes to remove unlysed cell debris. After adding NaCl (0.5M) to the cell lysate, it was heated to 42° C. to aggregate REP.
  • Aggregated proteins were separated from the solution by centrifugation at 10,000 g at 40° C. for 15 minutes. The supernatant was removed, the pellet was dissolved in cold PBS buffer, and inverse transition cycling (ITC) was additionally performed to obtain high-purity REP protein.
  • ITC inverse transition cycling
  • Doxorubicin hydrochloride (58.0 mg, 0.1 mmol) was dissolved in anhydrous methanol (10 mL) in a round bottom flask.
  • 3-(2-pyridinyldithio)propanoic acid hydrazide [3-(2-pyridinyldithio)propanoic acid hydrazide, 27.5 mg, 0.12 mmole] dissolved in anhydrous methanol (2 mL) was added to the doxorubicin solution. . 3 drops of trifluoroacetic acid were added to the reaction mixture and the reaction stirred at room temperature overnight.
  • a REP protein-doxorubicin conjugate having the structure shown in FIG. 4 was prepared.
  • REP was dissolved in 20 mM PBS buffer (pH 7.4) to a final concentration of 10 mg/ml.
  • a 15-fold molar excess of doxorubicin hydrazone was dissolved in dimethylformamide, and a REP protein solution was added thereto, followed by reaction at room temperature overnight.
  • reaction solution was heated to 42°C and centrifuged at 3,000 rpm at 35°C for 10 minutes to separate the REP-doxorubicin conjugate from other reactants, and ITC was obtained using the characteristic of reversible phase change depending on temperature. As shown in FIG. 5, the REP-doxorubicin conjugate was purified.
  • Paclitaxel (1.28 g, 1.5 mmol), 3-(2-pyridinyldithio)propanoic acid [3-(2-pyridinyldithio)propanoic acid, 64.6 mg, 3.0 mmol] and DMAP (cat.) were dissolved in dichloromethane The dissolved solution was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 41.6 mg, 3.3 mmol], and the mixture was stirred at room temperature for 12 stirred for hours.
  • a REP protein-paclitaxel conjugate having the structure shown in FIG. 4 was prepared.
  • REP 60 mg, 0.001 mmol
  • 100 mM PBS buffer pH 7.4
  • 1 mM EDTA 1 mM EDTA
  • a 15-fold molar excess of 2'-[3-(2-pyridinyldithio)propanoyl]-paclitaxel was dissolved in dimethylformamide (2 ml), REP solution was added, and reacted at room temperature overnight.
  • the decontamination column containing PBS-EDTA was equilibrated with a PBS-EDTA solution and exchanged with a reaction buffer of REP-paclitaxel conjugate to remove by-products and excess unreacted reagents.
  • the REP-paclitaxel conjugate was purified by performing one ITC and then further purified by size exclusion chromatography using a PD-10 column equilibrated with PBS.
  • the purified REP-paclitaxel conjugate was concentrated to a final concentration of 100 ⁇ M and stored at -80°C.
  • the REP concentration was determined using the molar extinction coefficient of REP 5,690 Lmol -1 cm -1 , and the doxorubicin concentration was determined using doxorubicin absorbance and extinction coefficient 9,250 Lmol -1 cm -1 at 495 nm.
  • the REP concentration of the REP-doxorubicin conjugate was calculated using the absorbance at 280 nm according to the following formula except for the absorbance at 280 nm.
  • [REP] is the concentration of REP in the REP-doxorubicin conjugate.
  • the doxorubicin conjugate ratio was calculated by dividing the concentration of doxorubicin by the REP concentration.
  • the UV-vis spectrum of the REP-doxorubicin conjugate was confirmed at 15° C. from 800 nm to 200 nm using a Cary 100 UV-visible spectrophotometer.
  • the thermal transfer properties of the REP-drug conjugate were confirmed by observing the turbidity of the conjugate solution at 350 nm as a function of temperature using a Cary 100 UV-visible spectrophotometer with a temperature gradient of 1 °C/min.
  • the transition temperature (T t ) was defined as the 50% point of maximum turbidity, and the REP-drug transition temperature was fitted to the following equation.
  • T t a Ln([REP-Drug]) + b
  • [REP-Drug] is the REP-drug concentration
  • a is the slope
  • b is the T t of 1 ⁇ M of the REP-drug.
  • the protein concentration in PBS was 20 ⁇ M (the ratio of doxorubicin conjugate was 0.867), and the cooling rate was 1° C./mim.
  • PCNA-1 human pancreatic cancer cells were seeded in DMEM medium containing 10% FBS in a 96-well plate at a density of 2 ⁇ 10 4 cells per well, and cultured at 37° C. and 5% CO 2 conditions for 24 hours. After attachment for 24 hours, the culture medium was exchanged with DMEM (100 ⁇ L, without FBS) containing various concentrations of REP-doxorubicin.
  • REP-doxorubicin 5 ⁇ M and PANC-1 cells were incubated for 3 hours, and the internalization site of REP-doxorubicin was confirmed.
  • GRGDNP 100 ⁇ M
  • amiloride hydrochloride 1 mM
  • chloropromazine chlorpromazine, 50 ⁇ M
  • dynasore 80 ⁇ M
  • genistein 200 ⁇ M
  • the red fluorescence stained with REP-doxorubicin, the green fluorescence of LysoTracker Green staining the inside of the lysosome of the pancreatic cancer cells, and the blue fluorescence staining the pancreatic cancer cell nucleus were all combined in the fifth image to become yellow. As confirmed by fluorescence, it was confirmed that internalized REP-doxorubicin was present inside the lysosome.
  • REP-doxorubicin-treated tumor cells were treated with MitoTracker Green, which reacts specifically only to mitochondria, and observed under a fluorescence microscope. .
  • the endoplasmic reticulum encapsulating REP-doxorubicin through an integrin receptor-mediated mechanism moves into the pancreatic cancer cell and then fuses with the lysosome to transport REP-doxorubicin to the lysosome, and proteolytic enzymes inside the lysosome are REP- It was confirmed that doxorubicin was hydrolyzed into a small molecule peptide-doxorubicin to release peptide-doxorubicin into the cytoplasm, and the released small molecule peptide-doxorubicin conjugate penetrated into the nucleus and mitochondria to exhibit anticancer effects.
  • PANC-1 cells were treated with 10% FBS, 2 mM L-glutamine, 50 ⁇ g/mL streptomycin and 50 U/mL penicillin. Cultured in DMEM medium.
  • PANC-1 cells were cultured in a culture chamber at 37° C., 95% relative humidity and 5% CO 2 conditions.
  • PANC-1 cells were seeded at 2 ⁇ 10 4 cells per well in a medium containing 1% FBS in a 96-well plate and cultured for 24 hours. After allowing the cells to adhere for 24 h, the culture medium was replaced with fresh DMEM medium (100 ⁇ L, no FBS).
  • REP-doxorubicin was added to the wells so that the concentration of doxorubicin was 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.5, 5 and 10 ⁇ M, or the concentration of paclitaxel was 0.1, 0.25, 0.5, 1, 2.5, 5 , 7.5, 10, 50 and 100 nM REP-paclitaxel was added to the wells.
  • CCK-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] was added to each well, Incubated for 1 hour under % relative humidity and 5% CO 2 conditions.
  • IC 50 ( ⁇ M) values of doxorubicin, a mixture of REP and doxorubicin and REP-doxorubicin conjugate and drug resistance index of doxorubicin were confirmed in doxorubicin-sensitive MDA-MB-231 cells and doxorubicin-resistant MDA-MB-231 cells.

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Abstract

La présente invention concerne un conjugué de matrice extracellulaire (REP)-médicament anticancéreux, la matrice extracellulaire étant constituée d'un polypeptide de type élastine et d'un ligand de récepteur d'intégrine, et son utilisation médicale. Le conjugué de matrice extracellulaire (REP)-doxorubicine présente une activité anticancéreuse considérablement améliorée par rapport à la doxorubicine ou à un mélange d'une REP et de doxorubicine, et il a été confirmé que le conjugué a pour effet de supprimer la pharmaco-résistance de cellules cancéreuses qui présentent une résistance à la doxorubicine. Ainsi, le conjugué de matrice extracellulaire (REP)-doxorubicine peut être fourni en tant que composition pharmaceutique pour supprimer la pharmaco-résistance de cellules cancéreuses qui présentent une pharmaco-résistance vis-à-vis d'agents thérapeutiques anticancéreux et de médicaments anticancéreux, qui sont efficaces pour le traitement de maladies cancéreuses.
PCT/KR2020/015525 2020-01-15 2020-11-06 Conjugué constitué d'une matrice extracellulaire et d'un médicament anticancéreux, et son utilisation médicale WO2021145543A1 (fr)

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Citations (2)

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WO2007090094A2 (fr) * 2006-01-27 2007-08-09 The University Of Mississippi Medical Center Administration thermiquement ciblee de medicaments comme la doxorubicine
US20130310538A1 (en) * 2005-12-20 2013-11-21 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties

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WO2007092751A2 (fr) * 2006-02-03 2007-08-16 Eli Lilly And Company Composés et procédés pour moduler fxr

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US20130310538A1 (en) * 2005-12-20 2013-11-21 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties
WO2007090094A2 (fr) * 2006-01-27 2007-08-09 The University Of Mississippi Medical Center Administration thermiquement ciblee de medicaments comme la doxorubicine

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Title
JEON WON BAE, PARK BO HYUNG, WEI JUNJUN, PARK RANG-WOON: "Stimulation of fibroblasts and neuroblasts on a biomimetic extracellular matrix consisting of tandem repeats of the elastic VGVPG domain and RGD motif", JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A, JOHN WILEY & SONS, US, vol. 97A, no. 2, 1 May 2011 (2011-05-01), US, pages 152 - 157, XP055828699, ISSN: 1549-3296, DOI: 10.1002/jbm.a.33041 *
SARANGTHEM VIJAYA, CHO EUN A., BAE SANG MUN, SINGH THOUDAM DEBRAJ, KIM SUN-JI, KIM SOYOUN, JEON WON BAE, LEE BYUNG-HEON, PARK RANG: "Construction and Application of Elastin Like Polypeptide Containing IL-4 Receptor Targeting Peptide", PLOS ONE, vol. 8, no. 12, 1 January 2013 (2013-01-01), pages e81891, XP055828698, DOI: 10.1371/journal.pone.0081891 *
SAXENA RUBHA, NANJAN MOOLA JOGHEE: "Elastin-like polypeptides and their applications in anticancer drug delivery systems: a review", DRUG DELIVERY, ACADEMIC PRESS, ORLANDO, FL., US, vol. 22, no. 2, 17 February 2015 (2015-02-17), US, pages 156 - 167, XP055828700, ISSN: 1071-7544, DOI: 10.3109/10717544.2013.853210 *

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