Research On Construction Of ROS-sensitive Polymeric Drug Delivery Vectors And Their Application For Disease Treatment

The burgeoning nanotechnology has enabled nanomaterials to be so versatile in varied fields since the 21 st century.On the biomedicine front,the nano-drug system formed by the marriage of nanomaterials and drugs,promises a bright future for critical illness treatment.Nanocarrier,a novel drug delivery system,is free of problems caused by traditional drug delivery methods,which is more likely to prosper than fade.Advantages abound,one of which is that nanocarriers can be accurately released at the action site by virtue of active or passive targeting,avoiding the adverse effect of off-target effect on normal tissues.Also,it helps to prolong the blood circulation half-life period of drugs and enhance biocompatibility,as well as ameliorate the water solubility of hydrophobic drugs for the sake of better absorption due to drug degradation in the process of delivery.Moreover,in the light of the microenvironment characteristics of pathological tissues,drug-loaded nanoparticles in diverse types can be designed to realize the intelligent and efficient controllable release in targeted tissues.On this ground,the thesis falls into two projects,both of which are ROS responsive drug carriers designed for drug delivery(ROS refers to chemically active oxygen-containing substances).The main research contents and innovations can be unfolded as follows:Firstly,the triblock polymer — polyethylene glycol poly(2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxa-boron heterocyclopentane-2-yl)benzyl)oxy)carbonyl)oxy)ethyl methacrylate)-co-poly(2-(dimethylamino)ethyl methacrylate)mPEG-P(PBEM-co-DMA)— is designed and synthesized.It is evident that mPEG-P(PBEM-co-DMA)can be self-assembled into polymer micelles,which boast ROS sensitivity and are employed in pancreatic cancer therapy via loading DOX.In tumor tissue with high ROS concentration,the side chain of PBEM will break,and the hydrophobic group pinacol phenylborate will fall off,enabling the polymer to be hydrophilic.Thus,the disintegration of the polymer micelles supports the release of loaded drugs.The free drug DOX possesses better permeability in tumor tissues than nano drugs,realizing the effective drug therapy for avascular pancreatic cancer.As such,ROS responsiveness of drug-loaded micelles is demonstrated in vitro,and the safety of the carrier is also given credence.Secondly,the cationic polymer — polyethylene glycol-poly(aspartic acid(N,N diethylenediamine)-co-diethylenetriamine)(mPEG-PAsp(DEA-co-DETA)))— is designed and synthesized.In the initial stage,polyethylene glycol poly benzyl aspartate block polymer(mPEG-PBLA)is synthesized,and then block polymer(mPEG-PAsp(DEA-co-DETA)(or PAEE,for short)is obtained via the ammonolysis of the benzyl group on PAsp block by DEA and DETA.Numerous amino groups are applied to tip the balance in favor of the encapsulation of siRNA through the carrier,providing stronger protonation for its subsequent delivery as the polyaspartic acid is served as the main chain structure by PAEE and the modification of the side is done by DEA and DETA.Moreover,the surface of the siRNA-loaded nanodrug is handled in a coalescent way to cast off the impact of proteins and RNases in blood during the siRNA delivery by PAEE.Since the mentioned delivery,the residual amino group on the surface reacts with the double NHS ester of thioketal.The cross-linking structure can be a boon to realize stronger protection of siRNA drugs and prolong their blood circulation time,optimizing chances for passive targeting of nano drugs success.Simultaneously,thioketal linkage break in the ROS environment with high expression at the lesion,and the cross-linking structure is unlocked,assisting in the efficient release of the siRNA target.Hence,the cationic polymer is widely expected to become a new and better gene carrier.