Poly(Amino Acid)-based PH-sensitive Drug Delivery Vehicle:Synthesis And Antitumor Application

Poly(amino acid)polymers have broad application prospects due to their degradability,non-immunogenicity and good biocompatibility.In the field of medicine,poly(amino acid)nano-carriers with numerous molecular structures have been designed and synthesized,which had many the advantages,such as specific targeting,enhanced endocytosis,and controlled release of active drugs.Various nano-carriers based on poly(amino acid)materials become indispensable in new antitumor applications.In this paper,we design and synthesize two types of p H-sensitive copolymer as nano-drug delivery carriers base on poly(amino acid)s and methoxypolyethylene glycol(mPEG).The chemical structures of copolymers range from graft copolymers to block copolymers.The drug loading performance and the effect of inhibiting non-small cell lung cancer were evaluated.The antitumor hydrophobic drug podophyllotoxin is embedded by graft copolymer and block copolymer respectively.The drug-loading systems exhibit p H sensitivity and controlled release characteristic.The specific copolymers are following two types:(1)4-phenylbutanol-modified polyglutamic acid graft copolymer;(2)vinyl ethanol ether-modified polyaspartic acid block copolymer.(1)Polymeric micelles are extensively used for the delivery of hydrophobic drugs.Here we report a series of poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/ 4-phenylbutyl ester(PLG-g-mPEG / PB(PPB-1?PPB-4))copolymers,which was synthesized from 4-phenylbutanol(PB)and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)(PLG-g-mPEG)esterification.The chemical structures of PLG-g-mPEG / PB(PPB-1?PPB-4)and PLG-g-mPEG were characterized by1H-NMR and IR spectroscopy,which proved the existence of hydrogen bonds in PLG-g-mPEG and benzene ring in PLG-g-mPEG / PB(PPB-1?PPB-4).In this study,we demonstrate that the bonded PB enhanced micellar stability via circular dichroism(CD)and variable temperature infrared spectroscopy(VTIR).we investigated the micelle formation and stability in water by dynamic light scattering(DLS).With self-association process,podophyllotoxin(PPT)an effective anticancer agent was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed copolymers.A high drug loading capacity(28.2 wt %)were obtained.PPT-NPs micelles were stable at p H=7.4,and dissociated and released the encapsulated PPT in a weak acidicenvironment(p H 5.5).The proliferation of non-small cell lung cancer(A549)was significantly inhibited and confirmed by cytotoxicity assay.The acquired experimental data clearly demonstrated the optimization of the functional and structural features of polymeric micelles,which may become a promising formulation for cancer therapeutic applications.(2)After bonding with vinyl glycol ether,the polyaspartic acid block polyethylene glycol(mPEG-PAsp)is utilized to incorporate PPT with p H-sensitive acetal bonds.By in vitro release experiments,we find that the acetal bonds are extremely p H sensitive and has good drug loading and release efficiency.