Design And Synthesis Of Novel Platinum-Acetylide Conjugated Polymers For Biomedical Applications

Cancer has been one of the major threats to the health of human beings.The efficient and accurate cancer therapy has attracted growing research interests.Therefore,the development of highly efficient and multifunctional phototherapeutic agents is a key issue to achieve effective tumor therapy.Conjugated polymers?CPs?,as an emerging class of organic phototherapy agents,possess easy structural functionalization,excellent photostability and good biocompatibility,providing them as a promising class of materials for bioimaging,sensing,disease diagnosis and treatment.In addition,platinum?Pt?as a transition metal element,exhibits the high spin-orbit coupling constant,which promotes the rapid intersystem crossing of singlet-to-triplet.For instance,Pt-based complexes or nanoparticles have been widely used in tumor therapy or imaging.Importantly,when Pt?II?ion is conjugated with an alkyne unit,the Pt d-orbitals overlap with the p-orbitals of the alkyne unit,leading to an enhancement of?-electron delocalization and intrachain charge transfer,which generates the red-shifted absorption and improves the nonradiative decay from excited state to ground state.Based on the above consideration and easy functionalization of CPs,the Pt-acetylide building blocks and other photofunctional groups can be introduced into CPs through covalent bonds.Through the rational tuning of photoconversion behavior of CPs,we designed and synthesized new multifunctional Pt-acetylide CPs-based phototherapy agents to realize the imaging and treatment of tumors using excellent photoconversion behavior of phototherapy agents.Furthermore,a smart phototherapy platform loaded with singlet oxygen carrier has been used for in vivo hypoxic tumor therapy.The major contents of the thesis include the following parts:1.Design and synthesis of oxygen-responsive platinum?II?-acetylide conjugated polyelectrolyte for hypoxia imaging of cancer cellsA long-lived phosphorescent platinum?II?complex has been introduced into conjugated polyelectrolyte?CPEs?as the O₂-sensitive phosphorescent moieties,and the O₂-insensitive fluorescence from fluorene-based backbone can act as a reference.Due to the quaternized side chain,the amphiphilic polymers P2 can form conjugated polyelectrolyte dots?CPE-dots?with the size of 3nm through self-assemby in water,which have been used as dual-emissive O₂ probes.The ratiometric measurements of hypoxia were carried out in living cells.Furthermore,O₂ levels in living cells have been investigated through time-resolved luminescence imaging?TRLI?.Importantly,TRLI can minimize the short-lived fluorescence interference and improve the signal-to-noise ratio,increasing the accuracy of O₂ sensing in cancer cells.2.Design and synthesis of near-infrared platinum?II?-acetylide conjugated polymers for tumor phototherapyA novel near-infrared?NIR?Pt-acetylide conjugated polymer CP3 with highly efficient photoconversion behaviors for synergistic phototherapy was designed and synthesized.After the introduction of Pt into CP3,the triplet state,which benefits the generation of reactive oxygen species for photodynamic therapy,was identified clearly in both CP3 and the prepared CP3 nanoparticles?CP3-NPs?by the ultrafast femtosecond transient absorption?fs-TA?spectroscopy.Furthermore,different from the traditional nonradiative decay channel with lifetime of 1.1 ps in CP3,CP3-NPs possess an additional nonradiative decay channel with lifetime of 10 ps,both of which contribute to the excellent photothermal conversion effect.Therefore,CP3-NPs can achieve the preferable conversions into both remarkable singlet oxygen generation and photothermal effect for PA imaging-guided synergistic phototherapy.The fundamental understanding of the excited-state dynamics in Pt-acetylide CPs will provide valuable guideline for the future design of high-performance theranostic agents based on CPs for synergistic cancer phototherapy.3.Design and synthesis of photothermally-responsive conjugated polymeric singlet oxygen carrier for hypoxic tumor phototherapyA novel photothermally-responsive conjugated polymeric singlet oxygen?¹O₂?carrier,achieving phase-change-controlled and fluorescence imaging-guided sustainable phototherapy for hypoxic tumor,has been designed and prepared.Firstly,Pt-acetylide conjugated polymers?CPs?containing boron dipyrromethene?BODIPY?units with strong NIR absorption were chosen as a perfect phototherapeutic platform,which simultaneously possess photodynamic therapy?PDT?and photothermal therapy?PTT?properties.Secondly,1,4-dimethylnaphthalene,as the efficient ¹O₂carrier,was introduced into CPs?CP4?,which can reversibly trap and photothermally release ¹O₂,providing a new strategy for directly delivering ¹O₂ to relieve hypoxic tumor.The CP4 nanocarriers?CP4-NPs?were prepared through co-encapsulating hydrophobic CP4 in biocompatible organic phase-change materials?PCM?with amphiphilic lecithin and DSPE-m PEG₅₀₀₀.Meanwhile,the novel CP4-NPs were injected into tumor-bearing mouse through tail vein and accumulated in the tumor location via the enhanced permeability and retention effect.Besides,the CP4-NPs could not only serve as a NIR luminescence imaging contrast agent but trap the ¹O₂ produced from CP4 under irradiation and form a stable endoperoxide?EPO?.Furthermore,the EPO undergoes cycloreversion to controllably release ¹O₂ via the NIR light-induced photothermal effect of CP4 and controlled phase-change of PCM,which can be used for oxygen-independent phototherapy for hypoxic tumor.Therefore,the present study demonstrates the potential of CP4-NPs in sustainable cancer phototherapy,providing valuable guideline for developing high-performance theranostic agents in cancer treatment.