| Malignant neoplasm has become one of the greatest threats to human health, whilechemotherapy has a pivotal position among several treatment programs. The clinicaluse of Cisplatin, a small molecule broad-spectrum chemotherapeutic drug, shows agood efficacy in both chemotherapy alone and combination chemotherapy. But thereare obvious defects such as non-specific, no targeting, short half-life in vivometabolism, low utilization, high systemic toxicity， and easy to produce drugresistance, etc. Therefore the therapeutic effect of Cisplatin is limited and thetherapeutic index is low, which hinder its broad-spectrum application. Since the riseof nanotechnology in20thcentury, a large number of biodegradable andbiocompatible polymer materials are developed, thus has boosted the research anddevelopment of anti-tumor drugs with the delivery system based on polymernanotechnology, which could overcome the above defects of Cisplatin. Polymer nanomaterial has the advantages of the traditional drug delivery system such as highsolubility and stability, and the character of sustained release. Moreover, it couldsignificantly alter the tissue distribution and metabolism of drugs, improve efficacyand reduce side effects, which has a great value to clinical application. The mostnotable is that the vascular is richer and the endothelial cell gap is much larger intumor lesion than in normal tissue, causing macromolecular substances andnanoparticles have selective Enhanced Permeability and Retention Effect (EPR effect)at the tumor sites. Therefore, polymer nano drug enters by passive transport whencirculating to the tumor tissue. It could also effectively prolong drug circulation timein the body and better play the EPR effect of drug-loader, which maximizes theefficacy at the target lesion site.Based on the polymer nano-technology mentioned above, taking biodegradablepoly(ethylene glycol)-poly(L-glutamic acid) polymer as the loader of Cisplatin, wemade cisplatin-loaded poly(ethylene glycol)-poly(L-glutamic acid) nanoparticlesThereafter we investigated the aspects of stimuli-responsive release, efficacy of reducing toxicity effect, compatibility alliance with different small molecule drugs,and targeted delivery of nano drugs. In details:1. Loading Cisplatin based on poly(ethylene glycol)-poly(L-glutamic acid) polymer,we made the nano-particles platinum drug with the core of polyglutamate-platinum（II） and the shell of polyethylene glycol. The diameter of the nanoparticle is about35nm. It could achieve a slow steady release of the platinum drug in physiologicalsaline. In the liver and kidney toxicity and blood test of Kunming Mice, the index ofALT、AST、CREA、BUN、WBC、PLT in nano-Cisplatin group showed lesssignificant increase or decrease than in Cisplatin group, showing that Cisplatinnanoparticles reduced the toxic effect. In the treatment of mice’s subcutaneousxenografts of lung cancer, Cisplatin nanoparticles could effectively inhibit the growthof tumor, and significantly reduced the systematic toxicity of Cisplatin. There wasweight decrease phenomenon in Cisplatin group while no in nano-Cisplatin group,showing Cisplatin nanoparticles has low toxic effect and more obvious targetingrelease effect. In the IHC analysis of tumor tissue after treatment, the numbers ofapoptosis in two groups were equal. In Hematoxylin-eosin staining analysis, nano-Cisplatin group showed no pathological anomalies as in Cisplatin group.2. We investigated the efficacy of Cisplatin nanoparticles joint Combretaftation A-4P (CA4P) on mice with S-180sarcoma and did vitro assessment on cytotoxicity ofhep-2、S-180、Lewis cells. Poly (L-amino acid) graft poly (ethylene glycol)copolymer had no cytotoxic. In vivo experiments, compared to Cisplatin, Cisplatinnanoparticles combining Anti-angiogenesis blockers Combretaftation A-4P showedsignificant increase of efficacy and decrease of toxicity on mice with S-180sarcoma.This combination program provides new treatment for clinical application. At thesame time it proves the better anti-tumor efficacy of Cisplatin nanoparticles.This study could promote the research and development of anti-tumor drugs withloader of biodegradable poly(ethylene glycol)-poly(L-glutamic acid) polymer andbecome foundation of the biodegradable polymer applied to controlled release ofanticancer drugs... |
PDF Full Text Request