A THERMALLY RESPONSIVE SHORT ELASTIN LIKE POLYPEPTIDE-DRUG CONJUGATE: SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION FOR TARGETED DELIVERY OF ANTICANCER DRUGS
Keywords:Anticancer drug, Drug delivery system, Drug targeting, Elastin like polypeptide, Drug conjugate
Introduction: Among the several new strategies explored today to avoid the side effects in cancer chemotherapy. The concept of polymer-drug conjugates has shown considerable promise. In this context, genetically engineered long elastin like polypeptides (ELPs) have been examined recently as drug carriers. These ELPs, however, have certain limitations.
Objective: It is our hypothesis that short synthetic ELPs can also be used as drug carriers so as to overcome these limitations. The purpose of this investigation was, therefore, to synthesize, characterize and evaluate a thermally responsive short ELP-Doxorubicin conjugate for targeted delivery.
Methods: The ELP-Doxorubicin conjugate of molecular weight 1280 Da was synthesized and characterized by ESI-MS, FTIR and NMR studies. Turbidimetry, differential scanning calorimetry (DSC) and circular dichorism (CD) studies were carried out to evaluate its structural transition behavior. Cellular uptake and intracellular localization studies of the conjugate and the free drug were carried out by flow cytometry and confocal fluorescence microscopy, respectively. In vitro cytotoxicity of the conjugate was evaluated by the MTT assay method and compared with that of the free drug.
Results: The results reveal that the short ELP synthesized exhibits structural transition behavior similar to naturally occurring long ELPs and delivers more drug molecules to intracellular space compared to the free drug. This structural transition behavior can also be exploited for targeting drugs to solid tumors using hyperthermia.
Conclusion: As hypothesized our investigations clearly demonstrate that short thermally responsive ELPs are good carrier for targeting anticancer drugs to the intracellular space.
Jain A, Jain A, Gulbake A, Hurkat P, Jain SK. Solid tumors: A review. Int J Pharm Pharm Sci 2011;3(5):45-51.
Duncan R. Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 2006;6(9):688-701.
Atkins JH, Gershell LJ. Selective anticancer drugs. Nat Rev Drug Discov 2002;1(7):491-2.
Huang PS, Oliff A. Drug-targeting strategies in cancer therapy. Curr Opin Genet Dev 2001;11(1):104-10.
Moses MA, Brem H, Langer R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell 2003;4(5):337-41.
Duncan R, Vicent MJ. Polymer therapeutics-prospects for 21st century: The end of the beginning. Adv Drug Deliv Rev 2013;65:60-70.
Meyer DE, Kong GA, Dewhirst MW, Zalutsky MR, Chilkoti A. Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia. Cancer Res 2001;61(4):1548-54.
Raucher D, Chilkoti A. Enhanced uptake of a thermally responsive polypeptide by tumor cells in response to its hyperthermia-mediated phase transition. Cancer Res 2001;61(19):7163-70.
Furgeson DY, Dreher MR, Chilkoti A. Structural optimization of a smart Doxorubicin polypeptide conjugate for thermally targeted delivery to solid tumors. J Control Rel 2006;110:362-9.
Bidwell GL, Davis AN, Fokt I, Priebe W, Raucher D. A thermally targeted elastin like polypeptide doxorubicin conjugate overcomes drug resistance. Invest New Drugs 2007;25:313-26.
Bidwell GL, Fokt I, Priebe W, Raucher D. Development of elastin like polypeptide for thermally targeted delivery of doxorubicin. Biochem Pharmacol 2007;73:620-31.
Dreher MR, Raucher D. Evaluation of an elastin like polypeptide-doxorubicin conjugate for cancer therapy. J Control Rel 2003;91:31-43.
Matsumura Y, Maeda A. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986;46(12):6387-92.
Langer R. Drug delivery and targeting. Nat 1998;392:5-10.
Jain RK. Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. J Natl Cancer Inst 1989;81(8):570-6.
Jain RK. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev 2001;46(1-3):149-68.
Nicolini C, Ravindra R, Ludolph B, Winter R. Characterization of the temperature and pressure induced inverse and reentrant transition of the minimum elastin like polypeptide GVG(VPGVG) by DSC, PPC, CD and FT-IR spectroscopy. Biophys J 2004;84:1385-92.
Nuhn H, Klok HA. Secondary structure formation and LCST behavior of short Elastin like peptides. Biomacromolecules 2008;9:2755-63.
Chabner BA, Longo DL. Cancer chemotherapy and biotherapy: principles and practice. New York, 3rd eds. Philadelphia: Lippincott Williams and Wilkins; 2001.
Saxena R, Nanjan MJ. A simple and efficient symthesis of 3-2 pyridinyldithio propanoic acid hydrazide: a heterobifunctional crosslinker. Int J Pharm Pharm Sci 2012;4(4):557-9.
Fields GB, Noble RL. Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 1990;35:161-214.