Study On The Preparation, Controlled Release And Cytotoxicity Of Poly (Aspartic Acid) Derivatives-CDDP Prodrugs

Polymer prodrug is a new type of macromolecular drugs in which polymers are used as carriers for the drug delivery.Several polymeric drugs have been successfully studied in clinical trials.Recently,interest in polymeric drugs with low toxicity and long-circulation has increased remarkably.Polymer drugs generally exhibit prolonged half-life,higher stability,water-solubility,lower immunogenicity and antigenicity and also specific targeting to tissues or cells.Polymer drugs are already in the market for the treatment of different diseases,demonstrating the potentials of the technology.We have synthesized a new series of poly(aspartic acid) derivatives as carriers of CDDP, and studied the drug loading,controlled release and cytotoxcity of polymer-CDDP anticancer drugs.The details are given as follows.Chapter 1:IntroductionFor decades,the delivery of small molecular anticancer drugs using polymeric materials has attracted considerable attention from polymer chemists,chemical engineers,and pharmaceutical scientists.The review of the chapter will discuss the progress of polymer drugs and the mechanism of the polymer drugs treating diseases, especially the anticancer polymer drugs.Chapter 2:Synthesis and characteristic of poly(aspartic acid) derivatives as new drug carriersIn this chapter,polymer carrierâ… :With the aid of water/triethylamine as solvent,α,β-Poly((N-succinyl)-D,L-aspartamide)(PSAA) was successfully synthesized by ring cleavage reaction of L-asprtic acid to polysuccinmide in a homogeneous system at room temperature,and characterized by FTIR and ¹H NMR.The influence of volume ratios of water to triethylamine on the reaction was evaluated.Polymer carrierâ…¡:graft copolymers,mPEG-g-α,β-poly((N-amino acidyl)-D,L-aspartamide)(mPEG-g-PAAsp) were synthesized by the ring-opening reaction of polysuccinimide with mPEG-NH₂(Mw:2000 and 5000 Da),and then with L-aspartic acid and L-glutamic acid,respectively,and characterized by FTIR and ¹H NMR.Chapter 3:Synthesis and in vitro cytotoxicity ofα,β-poly((N-succinyl)-D,L-aspartamide)-CDDP macromolecular prodrugPSAA-CDDP and PAsp-CDDP macromolecular prodrugs were prepared by conjugation of PSAA-CDDP andα,β-poly(L-aspartic acid)(PAsp) with cis-dichlorodiammine platinum(CDDP),respectively.Results showed that the cytotoxicity of PSAA or PAsp was rather low.Drugs could be released from PSAA-CDDP or PAsp-CDDP in a controllable manner.The in vitro cytotoxicity of PSAA-CDDP or PAsp-CDDP against Bel-7402 cells increased with increasing dosage,but was lower than that of CDDP with the corresponding dosage.The cytotoxicity was ranked as PAsp-CDDP＜PSAA-CDDP＜CDDP.Chapter 4:Fabrication of polymer-platinum(â…¡) complex nanomieelle from mPEG-g-α,β-poly[(N-amino acidyl)-DL-aspartamide]and cis-dichlorodiammine platinum(â…¡) and its cytotoxicityThe aim of research is to develop and optimize delivery system for cis-dichlorodiammine platinum(â…¡)(CDDP) based on polymer-metal complex nanomicelles with controllable particle size in order to achieve the passive tumor targeting.In particular,MPEG-g-PAAsp-CDDP complex nanomicelles were fabricated from mPEG-g-PAAsp and CDDR The formation of mPEG-g-PAAsp-CDDP nanomicelles was confirmed by fluorescence spectrophotoscopy,electrical conductivity and particle size measurements.It was found that all the nanomicelles showed spherical shapes with clear core-shell structures and narrow size distributions.Their sizes ranged from 80 to 160 nm, suggesting of their passive targeting potential to tumor tissue.With the increase of the molecular weight of mPEG,the sizes of mPEG-g-PAAsp-CDDP micelles showed a tendency to increase.MPEG-g-PAAsp-CDDP nanomicelles showed linear gradual drug release profiles in 40 h,suggestion of their sustained drug release behaviors. Compared with CDDP,mPEG-g-PAAsp-CDDP micelles showed essential decreased cytotoxicity to Bel-7402 cell line.