Design And Synthesis Of Conjugated Polymer Nanoparticles For Phototheranostics

Phototheranostics is a non-invasive medical technology to achieve diagnosis and treatment of disease using photonics principles and optical technology,and it is becoming an important supplementary technology in diagnosis and treatment of major diseases including cancer.Development of high performance phototheranostic agents is of great significance for improving the phototherapeutic efficacy.However,there are still some critical issues which should be addressed.For example,the therapeutic efficacy of phototheranostic agents needs to be further improved.For photothermal therapy(PTT),the overexpression of heat shock proteins(HSPs)may alleviate the damage of heat to tumor cells,leading to the reduced therapeutic efficacy.For photodynamic therapy(PDT),the hypoxic microenvironment of tumor tissue significantly restricts the efficacy of PDT.Meanwhile,the biosafety of phototheranostic agents is a critical issue which hinders the clinical applications of most agents.Until now,some phototheranostic agents have potential toxicity,and they are difficult to be metabolized or degraded.These agents may retain in the body for long period of time and induce long-term toxicity.Thus,improving the therapeutic efficacy and biosafety of phototheranostic agents is of great significance.Among various kinds of optically functional materials,conjugated polymers possess high photostability,large molar extinction coefficient and good biocompatibility.Moreover,conjugated polymer nanoparticles constructed by conjugated polymers have good tumor accumulation capability,showing their great potential in the field of phototheranostics.Thus,conjugated polymer nanoparticles-based phototheranostic agents have attracted more and more attention.Centered on the above issues of phototheranostic agents,in this thesis,three phototheranostic nanosystems based on conjugated polymer nanoparticles are developed.1.Conjugated Polymer Nanoparticles for NIR-Ⅱ Fluorescence Imaging-Guided Photothermal/Thermodynamic Combination TherapyTo improve the efficacy of PTT,a nanosystem(ADPPTN)for photothermal/thermodynamic combination therapy based on conjugated polymer nanoparticles is designed.ADPPTN is prepared by encapsulating NIR-Ⅱ fluorescent conjugated polymer DPPT into carboxyl group decorated amphiphilic copolymer PSMA-PEG,followed by loading a water soluble azo-containing compound AIPH via electrostatic interaction.ADPPTN can accumulate into tumor site via EPR effect during circulation.Under 808 nm laser irradiation,DPPT in the nanoparticles can generate heat to conduct PTT,and the heat may further trigger the decomposition of AIPH,achieving thermodynamic therapy.In addition,the NIR-Ⅱ fluorescence signal of ADPPTN can light the tumor and delineate the margin of tumor tissue.Compared with the nanoparticles without AIPH loading(DPPTN),ADPPTN shows better anticancer efficacy both in vitro and in vivo.The azo initiator loaded nanosystem developed in this work achieves photothermal/thermodynamic combination therapeutic,and provides new method to overcome the drawbacks of PTT.2,Iodine-Rich Conjugated Polymer Nanoparticles for CT/Fluorescence Dual-Modal Imaging-Guided Enhanced Photodynamic TherapyTo improve the efficacy of PDT,an iodine-rich conjugated polymer nanoparticles-based nanotheranostic system SPN-Ⅰ is designed.SPN-Ⅰ is prepared by encapsulating a hydrophobic conjugated polymer PCPDTBT into an iodine-grafted amphiphilic copolymer PEG-PHEMA-I.A conjugated polymer nanoparticles without iodine-decorating,SPN-P,is prepared by F127 encapsulation as the contrast.Owing to the intermolecular heavy-atom effect,the singlet oxygen quantum yield of SPN-Ⅰ is 1.5-fold higher than that of SPN-P.Furthermore,because of the high X-ray attenuation coefficient of iodine,SPN-Ⅰ is a good candidate for CT imaging contrast agent.Thus,SPN-Ⅰ can achieve CT/fluorescence dual modal imaging.In vitro cytotoxicity study indicates that SPN-Ⅰ has a better anticancer effect than SPN-P under laser irradiation.SPN-Ⅰ may effectively accumulate into tumor site via EPR effect,and light tumor via CT/fluorescence dual modal imaging.In vivo study shows that SPN-Ⅰ has a better tumor inhibition rate than SPN-P under laser irradiation.This work develops a facile method to enhance the PDT efficacy via the intermolecular heavy-atom effect,which provides new insight for overcoming the disadvantage of PDT.3,Biodegradable Conjugated Polymer Nanoparticles for Second Near-Infrared Fluorescence ImagingTo reduce the toxicity of contrast agent,random copolymer CP-50 is synthesized via replacing50% vinyl moiety of polyphenylene vinylene(PPV)with diketopyrrolopyrrole(DPP)moiety.DPP endows CP-50 with NIR-Ⅱ fluorescence property,while PPV endows CP-50 with biodegradation property.CP-50 is encapsulated into amphiphilic copolymer PEG-b-PPG-b-PEG to form water-soluble nanoparticle CPN-50 with good cell internalization and cytocompatibility.CPN-50 can be degraded in biomimicking environment.In vivo NIR-Ⅱ imaging experiment demonstrate that CPN-50 can be nearly completely metabolized by liver in 20 days.Besides,CPN-50 can accumulate in tumor and achieve effective tumor imaging.This work successfully synthesized biodegradable NIR-Ⅱ fluorescent conjugated polymer via electron withdrawing units doping,thus provides a new approach for addressing biosafety issue of phototheranostic agents in bioapplications.