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Synthesis and Applicaiton of Platinum Drug Loaded Polymer Carrier

Author: CaiHaiDong
Tutor: GengAiFang
School: Changchun University of Science and Technology
Course: Physical and chemical
Keywords: Biodegradable Polymer Platinum Drugs Drug Delivery
CLC: TQ460.1
Type: Master's thesis
Year: 2013
Downloads: 2
Quote: 0
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Abstract


Chemotherapy, resectional therapy and radiotherapy are generally so-called three major cancer therapies. Among a variety of anticancer drugs, platinum drugs are overwhelmingly important, the usage of them occupies more than a half of all the anticancer drugs hence they are believed to be enormously and widely used.In clinic, the most applicable Pt drug is Cisplatin, which is a non-specific cell cycle anticancer drug and is supposed to crosslink with DNA to damage its replica and ultimately induces cell apoptosis. Cisplatin has a broad anticancer spectrum and it is mostly synergistic and non-cross-resistant with other anticancer drugs. Cisplatin is widely used to treat solid tumors such as ovarian cancer, prostatic cancer, testicular cancer, lung cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma and breast cancer. However, limited water solubility, serious side effects of digestive tract, bone marrow suppression, auditory toxicity and irreversible damage to kidneys restrict its further development.The efforts in reducing the toxicities and side effects of cisplatin never halt and even accompanies its discovery since1969by Rosenberg. At the end of last century, more safe platinum drugs such as carboplatin, oxaliplatin were developed to relatively alleviate the side effects to reach better clinic effects.Classic small molecules based anticancer drugs including Pt drugs suffer from a variety of problems such as diffusion distribution in vivo, rapid metabolic elimination, great punctuation of drug concentration and many side effects. Recently, polymer drug conjugate was conceived and proposed to enhance the pharmacokinetics of anticancer drugs. Polymeric drugs with peculiar characteristics of protecting drugs from premature drug release, which can reduce the drug damage to normal tissues have gained great and extensive attention from around the world. Polymer conjugate drugs or polymer pro-drugs which consist of macromolecular drug carrier and loaded drugs exert their efficacy by releasing active anticancer species once they reach the tumor site. Extensive studies on polymeric drug delivery systems have been made since the concept of "polymer drug" was proposed. However, there still lacks of a systematic research on polymer based platinum drugs till far.Based on the structure and activity relationship of Pt drugs as well as technology of the polymer drug conjugates, this dissertation aims to combine the latest and cutting edge technology in nano-medicine and the widely used Pt drugs by designing one of Pt drugs and thereafter attaching it to biodegradable polymers to prepare polymer platinum drug delivery systems. Moreover, systematic study on the physiochemical characteristic and the anticancer efficacy of the polymer platinum drugs were performed in vitro and in vivo. The major aspects could be summarized as belows:(1)Akind of micromolecule drugs, Pt (Ⅱ) was synthesized and the structures of the newly synthesized Pt drugs were confirmed by1HNMR, IR and ESI-MS, etc.(2)Synthesizing functionalized biodegradable polymers with pendant mono-carboxyl group,1,2-bidendate carboxyl groups, hydroxyl group; preparing Nile blue labeled polymers for fluorescence imaging or confocal laser microscopy;1H NMR, GPC, etc were used to confirm the structure of the polymer designed;(3)Successfully chelating the Pt (Ⅱ) drugs onto the biodegradable polymers with pendant mono-carboxyl group or1,2-bidendate carboxyl groups to prepare polymer platinum(Ⅱ) conjugates in which polymers were leaving groups of Pt(Ⅱ) drugs. The polymer platinum (Ⅱ) conjugates can be assembled into nanometer particles by itself. The assembled behaviour of nanometer particles was studied by TEM, DLS.(4)Through HPLC-ICP-MS, the release mechanism of polymer drugs was studied and then proposed; MTT assays revealed the IC50values against different cancer cells of the polymer platinum (Ⅱ) drugs;(5)Using the polymer platinum (Ⅱ) in the animal cells experiments domenstrates that the polymer plarinum (Ⅱ) is more effective and safer than micromolecular drugs.

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