Intelligent Responsive Polypeptide Nanoparticles Systems For Near-Infrared Imaging-Guided Photodynamic

The complex physiology of tumor tissues,the development of intrinsic/acquired drug resistance and lack of tumor selectivity are some of the causes of failure of conventional cancer therapies,such as chemotherapy,radiotherapy and surgery.Photodynamic therapy(PDT),as a selective tumor treatment method,has minimal toxicity and aggressiveness to normal tissues.Designed biocompatible and biodegradable polypeptide nanoparticles for drug delivery,and selected a boron dipyrrole(BODIPY)photosensitizer with near-infrared imaging and high singlet oxygen generation capability as the fluorescent probe and PDT agent can realize the imaging-guided delivery of the drug in the body and the effective photodynamic therapeutic effect.In chapter two,studied the self-assembly of polymeric molecules for pH-sensitive nanoparticles is an especially important application in biology.Here,amphiphilic polypeptide copolymers are synthesized and spontaneously assembled to micelles in aqueous solution,and protonation of the tertiary amine groups in the side-chain of the copolymer under weak acid causes the micelle disassembly,which is pH sensitive,and the responsive pHs can be adjusted by addition of different salts.It is found that the Hofmeister ions play a key factor in controlling the subtle interaction of different noncovalent bonds among polypeptide molecules during their self-assembly or disassembly.The physical property exploration of the pH sensitive polypeptide nanoparticles may provide a new chance for the development of dynamic,complex nanostructures in various pH-responsive applications.In chapter three,to solve the problems of the photosensitizer leakage during blood circulation,poor accumulation in tumor tissue and inferior quantum yield of singlet oxygen.Herein,NHS-active boron-dipyrromethene derivative with bromine substituted NHS-BODIPY-2Br was first synthesized,which possessed high singlet oxygen generation efficiency and near infrared(NIR)fluorescence,and then it was conjugated to a sharp pH sensitive polypeptide to achieve a macrophotosensitizer for NIR imaging-guided PDT.Once accumulating in the tumor tissues,the nanoparticles can be demicellized by tumor acidity to promote cellular uptake,which could enlarge fluorescence signal intensity and enhance in vivo PDT therapeutic effect upon NIR laser irradiation.It provides a strategy to design photosensitizer conjugated tumor acidity sensitive polypeptide for NIR imaging-guided photodynamic therapy.Mannose has been reported as a novel drug to kill cancer cells.The prodrug of mannose will promote its targeted delivery and enrichment at the tumor site and cancer cells.Here in chapter four,a pH-sensitive polypeptide copolymer with a tertiary amine group has been prepared and a mannose molecule was conjugated to the polymer through the formation of a Schiff base.At the same time,an iodinated boron dipyrromethene(BDPI)photosensitizer with high singlet oxygen generation efficacy and near infrared(NIR)fluorescence was encapsulated by the nanoparticles,which makes it a potential pH-sensitive NIR imaging-guided chemotherapy/PDT agent.In vitro and in vivo studies reveal that in a tumor acidic environment,the protonation of the tertiary amine group destroyed the nanostructure of the nanoparticles,resulting in increased BDPI release.Meanwhile,the bond cleavage of the Schiff base led to the release of conjugated mannose and synergistic inhibition of tumor cell growth with the PDT effect was realized.The combination of these two kinds of tumor suppression effects and photodynamic therapy made this pH-sensitive polypeptide delivery system show great potential for further cancer therapy.In chapter five,because a major hindrance for photodynamic therapy(PDT)to achieve higher efficiency is the hypoxia environment in the tumor area and the PDT-induced continuous consumption of molecular oxygen.Oxygen self-sufficient fluorinated polypeptide nanoparticles have been synthesized via the loading of a NIR photosensitizer(BODIPY-2Br)into a water-dispersible drug delivery system for high efficiency PDT.As a result of the higher oxygen capacity and 1O2 lifetime enhancement of perfluorocarbon,the whole PDT agent demonstrated higher oxygen uptake and enhanced singlet oxygen production,showing the potential to improve the PDT efficacy in hypoxia tumor environments after light irradiation.Results demonstrated that the fluorinated polypeptide platform plays a significant role as an effective delivery vehicle for small molecule photosensitizers while increasing the generation of reactive oxygen species(ROS)and having higher cytotoxicity to cancer cells,especially in the hypoxia environment.In addition,the BODIPY-2Br photosensitizer work for both PDT agent and imaging in the NIR region making the nanoparticles a potential theranostic for cancer treatment.Mitochondria has critical function in sustaining cellular viability and death,which is the ideal organelle for PDT.Here in chapter six,we reported a tetraphenylporphine(TPP)conjugated amphiphilic copolymer and an iodinated boron dipyrromethene photosensitizer(BDPI)with high singlet oxygen yield to form nanoparticles(PBDPI-TPP),which could realize mitochondria targeting and improve NIR imaging-guided PDT.The as-prepared mitochondria targeting nanoplatform could show effective subcellular localization and bring about significant irreversible mitochondrial injury for enhanced PDT.Both in vitro and in vivo experiments revealed that the mitochondria targeting PDT system could achieve a remarkable therapeutic effect indicated that it is a promising nanoplatform for NIR imaging-guided PDT in cancer therapeutics.In this paper,polypeptides with biocompatibility and biodegradability were prepared,and photosensitizer BODIPY with excellent optical properties was designed.A series of smart nano drug-loading systems with targeting and stimulus response characteristics were designed to imaging-guided therapy.