Synthesis,Self-assembly And Anti-tumor Activity Of Amphiphilic Camptothecin Prodrugs

Conventional small molecule chemotherapy drugs usually suffer from several limitations including rapid blood/renal clearance,poor water-solubility,severe side effects for healthy tissues,bad selectivity and multi-drug resistance(MDR),et al.To challenge these limitations,nanodrug delivery systems were developed very quickly in recent years.With the help of these nanovectors,the biocompatibility of hydrophobic anticancer drugs increased greatly.The side effects of drugs reduced and the small molecule anticancer drugs could be delivered selectively to the tumor site.However,most of nanovectors had very low drug loading capacity and limited therapeutic efficacy.Even worse,nanocarriers may cause high toxicity and serious inflammation to kidney or other healthy organs in the body.Therefore,the construction of a nano-sized delivery system for anticancer drug has great potential application in the clinic,which could effectively solve the above problems.In this paper,two kinds of amphiphilic camptothecin prodrug were synthesized,which consisting of a hydrophilic anticancer drug and a hydrophobic anticancer drug linked by a disulfide bond.Additionally,the prodrugs could self-assemble into nanowires in aqueous solution,which as a carrier-free nanodrug delivery system was evaluated as well.The main contents and conclusions are described as follows:(1)Synthesis,self-assembly and in vitro anti-tumor activity of CPT-ss-Ir.We propose a novel method that uses Irinotecan(Ir),an FDA approved hydrophilic derivative of camptothecin(CPT),to conjugate CPT through a redox-responsive linker to compensate the extreme hydrophobicity of CPT.The molecular structure of CPT-ss-Ir was characterized by ~1H NMR and mass spectrometry.CPT-ss-Ir with amphiphilic structure could self-assemble into unique nanowire structure in aqueous solution through three kinds of methods.And the nanostructures were characterized by TEM.Moreover,the degradation behavior and drug release of CPT-ss-Ir nanowires were studied by fluorescence spectroscopy high performance liquid chromatography(HPLC),and TEM method.The results showed that the disulfide bonds in CPT-ss-Ir could be rapidly cleaved,followed by cyclization reactions to release Ir and CPT separately,accompanied by the disintegration of the nanowires under the reducing conditions.Furthermore,we observed the cellular uptake of CPT-ss-Ir nanowires using confocal laser scanning microscopy(CLSM),the results showed that CPT-ss-Ir nanowires could be internalized by MCF-7 cells efficiently.Finally,the anticancer activity of CPT-ss-Ir nanowires was estimated using MTT assays,the result shows that considerable cytotoxicity of CPT-ss-Ir nanowires in a variety of cell lines compared with the free CPT.(2)Synthesis,self-assembly and in vitro anti-tumor activity of CPT-ss-Gem.An amphiphilic drug-drug conjugate(CPT-ss-Gem)was synthesized also by disulfide bonds as linkers.And the molecular structure of CPT-ss-Gem was characterized by mass spectrometry and ~1H NMR.The CPT-ss-Gem can self-assemble into nanostructure in water because of its amphiphilic property.Furthermore,we compared the anticancer efficacy of CPT-ss-Gem nanowires and CPT/Gem mixture in combination chemotherapy in vitro.The results indicated that CPT-ss-Gem nano-prodrug presented a higher synergistic efficacy of CPT and Gem.Taken together,CPT-ss-Gem and CPT-ss-Ir,as carrier-free self-assembled nanodrugs could significantly improve the solubility and biocompatibility of hydrophobic drugs,which not only gets rid of the cytotoxicity concern of nanocarriers but also achieves high drug loading capacity.Therefore,they are expected to be a new generation of nanodrug formulation and provide very useful information for the design of nanodrug delivery system.