Nano-optical Probes Based On NIR-Ⅱ Conjugated Polymers For Tumor Multimodal Theranostics

Near-infrared（NIR）light excited phototheranostics,providing real-time,sensitive diagnosis and concurrent in situ phototherapeutics activated by photons due to the advantages of noninvasiveness and specific spatiotemporal selectivity.In phototheranostics,the light-based biomedical imaging,such as fluorescence imaging（FI）and photoacoustic imaging（PAI）,plays a crucial role in tumor diagnosis assessment clinically.Meanwhile,phototherapies,such as photothermal therapy（PTT）,photodynamic therapy（PDT）and light-triggered drug release,have received considerable attention.However,the design and research of current phototheranostic probes are mainly focused on the first near-infrared（NIR-I,650-900 nm）region.Compared with NIR-I light,the second near infrared light（NIR-Ⅱ,1000–1700 nm）possesses deeper tissue penetration and higher therapeutic effect.In addition,phototherapy is encountering huge challenges.On the one hand,the up-regulated heat shock proteins（HSP）expressed in tumor cells can partially repair heat damage,thereby reducing the efficiency of NIR-Ⅱ PTT.The hypoxia microenvironment of tumor can enhance stress resistance to PDT,reducing PDT efficiency.On the other hand,a single phototherapy modality cannot eradicate tumors with heterogeneous structures.More importantly,various therapeutic methods towards tumors only focus on primary tumor suppression without considering tumor metastasis or recurrence,leading to the high tumor mortality rate.Based on the above problems of phototheranostics,in this thesis,we designed and synthesized a series of nano phototheranostic probes based on NIR-Ⅱ conjugated polymers,exhibiting excellent NIR-Ⅱ imaging and PTT effect.The introduction of small molecule inhibitors can significantly inhibit and reduce HSP expression for improved PTT efficiency.Moreover,the combination of photothermal therapy and other treatment modalities further activates the anti-tumor immune response of the immune system and achieves effective elimination of primary and metastatic tumors.The thesis mainly includes the following three parts:1.NIR-Ⅱ Excitation Phototheranostic Probes for Bimodal Imaging Guided Photothermal-Photonic Thermodynamic TherapyThe limited light penetration depth,HSP-induced thermotolerance,and stress resistance induced by the tumor hypoxic microenvironment severely hinder the phototherapeutic effect.Herein,we prepared NIR-Ⅱ excitation phototheranostic nanoprobe Lip（PTQ/GA/AIPH）by incorporating NIR-Ⅱ conjugated polymer PTQ,azo compound AIPH,and HSP inhibitors（GA）into thermosensitive liposomes with targeted aptamer modification.The probe can realize multimodal phototheranostics of triple-negative breast cancer（TNBC）.After targeting the tumor,the nanoprobe was able to perform fluorescence/photoacoustic imaging-guided PTT under NIR-Ⅱ light excitation.NIR-Ⅱ PTT can trigger the release of HSP inhibitors,enhancing NIR-Ⅱ PTT efficiency through the inhibition of HSP activity.In addition,the hyperthermia induced by NIR-Ⅱ PTT can thermally decompose azo compounds and release cytotoxic free radicals to achieve photothermodynamic therapy（PTDT）effects.NIR-Ⅱ light excitation fluorescence/photoacoustic dual-modal imaging guided enhanced NIR-Ⅱ PTT and PTDT can achieve precise diagnosis and effective suppression of deep-seated TNBC.2.NIR-Ⅱ Fluorescence Imaging Guided Tumor-Specific Starvation Enhanced NIR-Ⅱ Photothermal TherapyInsufficient light penetration depth and cell thermoresistance severely reduce the photothermal therapeutic（PTT）effect.In this chapter,we utilized starvation-mediated thermosensation to specifically enhance NIR-Ⅱ PTT.We first synthesized a semiconducting conjugated polymer DPQ with excellent NIR-Ⅱ fluorescence imaging（FI）performance and NIR-Ⅱ photothermal effect.Then,2-deoxy-d-glucose（2DG）,as a glycolysis inhibitor,was coencapsulated into liposomes along with DPQ,to construct a NIR-Ⅱ phototheranostic probe Lip（DPQ+2DG）with folate modification.After folate-mediated targeting tumor cells,the probes could achieve NIR-Ⅱ FI guided NIR-Ⅱ PTT,and the photothermal effect could trigger the spatiotemporal release of 2DG.The released 2DG can inhibit tumor anaerobic glycolysis to deplete the energy supply of tumor cells,inducing severe tumor starvation.Furthermore,the concomitant starvation-induced decrease of ATP could hinder the production of intracellular HSP,thereby enhancing the thermosensitivity of tumors to PTT.The sensitization effect of 2DG significantly enhanced NIR-Ⅱ PTT therapeutic effect towards folate receptor-overexpressing tumor cells.This work provides a promising strategy for tumor-specific enhanced NIR-Ⅱ PTT.3.Self-Assembly Nanoadjuvant for Multimodal Imaging Guided Enhanced Tumor ImmunotherapyMultimodal theranostics induced immunotherapy efficiency are hindered by the complex tumor immunosuppressive microenvironment and low drug delivery efficiency of immunomodulators.Herein,a self-assembly nanoadjuvant（IMR NPs）with tumor microenvironment（TME）triggered cargo release,is designed and prepared for suppressing the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy（PTT and CDT）and immune remodeling.The nanoadjuvant is prepared through the self-assembly of ultra-small semiconducting polymer dots（IPodts）and toll-like receptor（TLR）agonist resiquimod（R848）utilizing manganese ions(Mn²⁺)as coordination nodes,for the efficient carrier-free delivery of Mn²⁺and R848.Under the tumor acidic condition,the nano-assembly can not only quickly release multiple therapeutic components for multimodal imaging（NIR-Ⅱ fluorescence/photoacoustic/magnetic resonance imaging）guided tumor photothermal and thermal amplification chemodynamic therapy,which are mediated by IPdots and Mn²⁺,respectively,but also can induce tumors immunogenic cell death（ICD）and evoke highly efficacious cancer immunosurveillance.More importantly,the released R848promotes the maturation of dendritic cells（DCs）,which amplifies the anti-tumor immune response together with the ICD induced by the synergistic therapy,thus effectively inhibiting tumor growth and lung metastasis.