PX_n Based Synthetic Nano Drug For Highly Efficient Anti-tumor And Anti-infective Therapy

Tumor and bacterial infection are two common diseases.With the rapid development of modern medical technology,the mortality continues to decline year by year.However,as a consequence of severe multidrug resistance(MDR),clinical treatments often end up failure,leading to a serious threat to the survival and health of human beings.Currently,accumulating evidence suggests that bacteria can infect specific tumor tissues,affect the development of tumors,and even mediate tumor resistance to chemotherapy drugs.Recnetly,host defense peptides(HDPs)and synthetic antimicrobial peptides(AMPs)designed to eradicate bacteria have also been shown to have similar cytotoxic activity against cancer cell,which could overcome the multidrug resistance through the physical membrane-disruption mechanism.However,the problems of high manufacture cost,toxicity and low stability in vivo limit its development and clinical application.Nowadays,peptide mimetic polymers have made considerable progress.While keeping the effect similar to antimicrobial peptide,those macromolecular polymers possess various advantages including versatile structure,low toxicity and easy for mass production,which have been endowed with great hope.Therefore,there is an urgent need to develop highly efficient anti-cancer and anti-microbial drugs capable of eradicating multidrug resistant problem while minimizing the onset of resistance.In this study,in order to obtain novel anti-tumor drugs with practical application value,a series of biodegradable guanidinium-functionalized polycarbonates with cationic properties were designed and synthesized firstly by simulating the structural features of natural antimicrobial peptides(AMPs).These macromolecular nanosized polymers exhibited a broad-spectrum of anti-bacterial activity in vitro and,at the mean time,possessed a pronounced lack of toxicity towards red blood cells.The polymer also demonstrated highly efficient antimicrobial activity and favorable selectivity towards a variety of clinically-isolated MDR bacteria.Unlike conventional antibiotics,repeated use of the polymers didn’t induce drug resistance due to their dual antimicrobial mechanism through membrane-translocation and membrane-disruption.Importantly,high in vivo treatment efficacy of the macromolecules is achieved in MDR A.baumannii-,E.coli-,K.pneumaniae-,methicillin-resistant S.aureus-induced peritonitis mouse model while remaining non-toxic.These macromolecules have tremendous potential as antimicrobials against MDR infections.Subsequently,in order to deploy these macromolecular nanosized polymers to anti-tumor study,we introduced a hydrophilic PEG block and a hydrophobic PLLA/PDLA block into the synthesized polymer structure,we got a series of ABC triblock copolymers capable of self-assembling in the liquid phase to form nanosized micellar structure.We used these nanoparticles as novel macromolecular chemotherapeutic agents.Interestingly,these self-assembled nanostructures exhibited a potent effect against various cancer cell lines even MDR cell in vitro and repeated use at IC50 concentration did not induce drug resistant.Through a series of mechanism studies,we demonstrated that cell death occurred mainly via a physical membrane-lytic mechanism.Fluorescence-labeled block copolymers were shown to be internalized by the cells and accumulated in the cytoplasm.The pharmacokinetics of polymers exhibited significantly prolonged circulation times with half-life of～2 h in the bloodstream,which was remarkably longer as compared with the first-line anticancer drug,doxorubicin(t1/2:～0.5 h).The polymers were found accumulating to a great extent in tumors after intravenous or intratumor injection,and the latter demonstrated an excellent antitumor effect in vivo without inducing significant systemic toxicity.Therefore,these macromolecular therapeutics can be used for both anti-tumor and anti-infection treatment without the onset of resistance,showing great application prospect.