Fabrication Of Targeted Cis-dichlorodiammine Platinum (Ⅱ) Micelles And Their Application In Therapy Of Tumor

Nanomedicine is a new type of drug in which nanoparticles are used as carriers for the drug delivery. Such nanomedicine can enhance anticancer effects compared with the drug they contain, while simultaneously reducing side effects, owing to properties such as more specific targeting to tumour tissues and active cellular uptake. Recently, polymeric micelles, which is one type of drug delivery systems, has been extensively studied due to having small sizes, good stability, targeting to tumour tissues and so on. Polymeric micelles are composed of an inner hydrophobic core and an outer hydrophilic shell. Hydrophobic drugs can be entrapped in the inner core by hydrophobic interaction, electrostatic effect and H-bond action, therefore solubility and bioavailability of the hydrophobic drug are increased. We have synthesized a new series of polymer-platinum(Ⅱ) complex micelles, and studied the structure, drug loading, sustained drug release, cytotoxcity and cellular uptake in vitro and anti-tumor efficacy in vivo. The details are given as follows.Chapter 1:IntroductionNanotechnology is multidisciplinary field and has been extensively studied. Nanotechnology offers a particular, paradigm-changing opportunity to make significant improvement in cancer diagnosis and treatment. In the last several decades, nanotechnology has been studied and developed mainly for use in novel drug-delivery systems. Although conventional medicines have good anticancer activity, the clinic use of these drugs are frequently hampered by poor water solubility, severely toxic side effects and so on. Nanomedicine has the potential to enable the preferential delivery of drugs to tumours due to the enhanced permeability and retention (EPR) effect, drug-circulation times, controlled drug release and specific binding of drugs to targets in cancer cells. The review of the chapter will discuss the progress of the nanomedicine and the mechanism of the nanomedicine treating diseases, especially the application of polymeric micelles in the oncotherapy field.Chapter 2:Fabrication and characteristic of polymer-platinum(II) complex micelles from mPEG/FA-PEG-g-a, P-poly [(N-amino acidyl)-aspartamide] and cis-dichlorodiammine platinum (Ⅱ)Fabrication of polymer-platinum(Ⅱ) complex micelles:FA-PEG-NH2 was initially prepared by activating the y-carboxyl group in folic acid for the conjugating to primary amine groups of PEG-diamine. And then, FA-PEG-g-PAAsp was particularly synthesized through ring-opening of PSI with FA-PEG-NH2 in DMF, then with potassium aminomalonate, L-aspartic acid or L-glutamic acid in the mixed solvent of water and triethyiamine. mPEG-g-PAsp-Ami was also synthesized according to the similar procedure. FA-PEG-g-PAAsp and mPEG-g-PAsp-Ami were characterized by 1H NMR. The characteristic of polymer-platinum(Ⅱ) complex micelles was confirmed by the methods of fluorescence spectrophotoscopy, ICP-AES, UV-vis, DLS and TEM.Chapter 3:Evaluation of polymer-platinum(Ⅱ) complex micelles from mPEG/FA-PEG-g-α,β-poly [(N-amino acidyl)-aspartamide] and cis-dichlorodiammine platinum (Ⅱ)Polymer-metal complex micelles fabricated from FA-PEG-g-PAAsp and CDDP showed sustained drug release behaviors over 40 h, their accumulative drug release was ranked at FA-PEG-g-PAsp-Ami-CDDP