Research Of Biodegradable Polymer Based Platinum Drugs

Cancer is a major desease threatening to human life and health. However,success has been limited to certain malignancies, and surgical intervention ispotentially curative for early stage patients. For the majority of patients with advancedstage of cancer, the treatment is limited to chemotherapy or radiation. Chemotherapyin particular has limitations due to the lack of selectivity with severe toxicity, andefficacy is very limited due to a lower dose. Chemotherapy, resectional therapy andradiotherapy are generally so-called three major cancer therapies. Among a variety ofanticancer drugs, platinum drugs are overwhelmingly important, the usage of themoccupies more than a half of all the anticancer drugs hence they are believed to beenormously and widely used.In clinic, the most applicable Pt drug is Cisplatin, which is a non-specific cellcycle anticancer drug and is supposed to crosslink with DNA to damage its replicaand ultimately induces cell apoptosis. Cisplatin has a broad anticancer spectrum and itis mostly synergistic and non-cross-resistant with other anticancer drugs. Cisplatin iswidely used to treat solid tumors such as ovarian cancer, prostatic cancer, testicularcancer, lung cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignantlymphoma and breast cancer. However, limited water solubility, serious side effects ofdigestive tract, bone marrow suppression, auditory toxicity and irreversible damage tokidneys restrict its further development.The efforts in reducing the toxicities and side effects of cisplatin never halt andeven accompanies its discovery since1969by Rosenberg. At the end of last century,more safe platinum drugs such as carboplatin, oxaliplatin were developed to relativelyalleviate the side effects to reach better clinic effects.Classic small molecules based anticancer drugs including Pt drugs suffer from avariety of problems such as diffusion distribution in vivo, rapid metabolic elimination,great punctuation of drug concentration and many side effects. Recently, polymerdrug conjugate was conceived and proposed to enhance the pharmacokinetics ofanticancer drugs. Polymeric drugs with peculiar characteristics of protecting drugs from premature drug release, which can reduce the drug damage to normal tissueshave gained great and extensive attention from around the world. Polymer conjugatedrugs or polymer pro-drugs which consist of macromolecular drug carrier and loadeddrugs exert their efficacy by releasing active anticancer species once they reach thetumor site. Extensive studies on polymeric drug delivery systems have been madesince the concept of “polymer drug” was proposed. However, there still lacks of asystematic research on polymer based platinum drugs till far.Based on the structure and activity relationship of Pt drugs as well as technologyof the polymer drug conjugates, this dissertation aims to combine the latest andcutting edge technology in nano-medicine and the widely used Pt drugs by designinga series of Pt drugs and thereafter attaching them to biodegradable polymers toprepare polymer platinum drug delivery systems. Moreover, systematic study on thephysiochemical characteristic and the anticancer efficacy of the polymer platinumdrugs were performed in vitro and in vivo. The major aspects could be summarized asbelows:(1) Synthesizing a series of Pt drugs including Pt(II), reduction-sensitive Pt(IV),photosensitive Pt(IV), multifunctional hybrid Pt(IV), multinuclear platinum(II) andmultinuclear platinum(IV) drugs; The structures of the newly synthesized Pt drugswere confirmed by1HNMR, IR and ESI-MS, etc.(2) Synthesizing functionalized biodegradable polymers with pendantmono-carboxyl group,1,2-bidendate carboxyl groups, hydroxyl group, amino groupand carbon carbon double groups; preparing FITC, Rhodamine B and Nile bluelabeled 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 withpendant mono-carboxyl group or1,2-bidendate carboxyl groups to prepare polymerplatinum(II) conjugates in which polymers were leaving groups of Pt(II) drugs. Thereleased Pt species were studied by HPLC-ICP-MS and XPS and the drug releasingmechanism was proposed; MTT assays revealed the IC50values against differentcancer cells of the polymer platinum(II) drugs;(4) Successfully conjugating reduction sensitive Pt(IV) drugs with cisplatin,carboplatin or oxaliplatin as precursors to biodegradable polymers by forming amideor ester linkages between the Pt drugs and the polymer. The so-obtained polymerplatinum(IV) conjugates were self-assembled into nano-micelles which displayed dualsensitivity to both acid and reducing agents. HPLC-ICP-MS and ESI-MS were furtherused to study the released Pt drugs and the drug releasing mechanism was proposed; MTT assays revealed that the polymer platinum(IV) drugs were more effective thanPt(II) drugs;(5) Successfully conjugating the photosensitive Pt(IV) drugs with cisplatin oroxaliplatin as precursors to biodegradable polymers. The so-obtained polymerplatinum(IV) conjugates can self assemble into micelles which demonstrate dualsensitivity to both UV irradiation and acid. ESI-MS, UV-vis studies on a series ofmodel drugs and releasing products of polymer platinum drug were performed toreveal the drug releasing profiles and mechanism; MTT assay showed thephotosensitive polymer platinum(IV) drugs are effective.(6) Based on the structure relationship of Pt drugs, multifunctional hybrid Pt(IV)drugs with other anticancer drugs, drug resistance inhibitors and anti cancersensitizers were creatively proposed and synthesized. With this method,multifunctional drug molecules can be precisely combined in one molecule. Moreover,the releasing of individual drugs can be modulated by attaching them to different sitesof the molecules because of the chemical reduction and hydrolysis mechanism Pt(IV)drugs; The multifunctional hybrid Pt(IV) drugs were further attached to the polymersto prepare polymer multifunctional Pt(IV) conjugates; Initial characterization on themwas performed.(7) Combination of the paclitaxel and daunorubicin with Pt(IV) drugs wasrealized in one polymer platform for the first time according to pre-existingtechnology of polymer-paclitaxel and polymer-doxorubicin conjugates as well as theabove mentioned polymer platinum(IV) conjugates. MTT assays and in vivo tumorinhibition experiment revealed the combination therapy in polymer platform wasmore safe and efficacious;(8) Based on the structure and activity relationship of mononuclear Pt(IV) drugs,the proof-of-concept multinuclear platinum(IV) drugs were proposed and prepared aspro-drugs of promising multinuclear Pt(II) drugs which have bottlenecks of beinghighly effective but highly toxic and then the multinuclear Pt(IV) drugs were furtherconjugated to polymers.