Combined Photodynamic Therapy Based On Polymeric Nanocarriers With Synergistic Effect

Photodynamic therapy(PDT)as a cancer treatment modality activates photosensitizers(PS)and transfers energy from PS to oxygen under the irradiation of light source,producing cytotoxic reactive oxygen species(ROS)and further oxidizing cancer cells to induce cellular apoptosis.As compared with traditional treatment modalities such as chemotherapy and radiotherapy,PDT possesses many advantages including non-invasiveness,low side effects,and high-efficiency ROS generation.However,the hypoxic microenvironment in tumor tissues severely limits the oxygen-dependent PDT.Moreover,PDT frequently meets the difficulties including recurrence of tumors and low tissue penetration of light.To overcome the disadvantages of PDT,in this paper,we constructed three nanoparticles with synergistic effects to improve the therapeutic efficacy of PDT.We prepared the hypoxia-responsive polyprodrugs with the combination of PDT for PDT-enhanced hypoxic environment to improve the therapeutic efficacy of combined PDT and chemotherapy.Novel Ⅰ/Ⅱ-type covalent organic frameworks(COF)nanoparticles were prepared to realize the high-efficiency PDT under hypoxia or normoxia upon exposure to light irradiation.The oxidation-responsive polyMOF nanoparticles were constructed for combination photodynamic-immunotherapy with enhanced STING activation.Overall,the paper contains the following three parts.1st Chapter:The inherent hypoxic microenvironment of solid tumors has an important influence on tumor growth,distant metastasis,and invasiveness.The heterogeneous distribution of hypoxic regions inside tumors limits the therapeutic efficacy of O2-assisted therapeutic strategy(e.g.PDT).On the other hand,the hypoxia-activable prodrugs cannot work effectively in the regions with enough O2 concentration.To address the issues,we prepare a block copolymer polyprodrug consisting of polyethylene glycol(PEG)and copolymerized segments of nitroimidazole-linked camptothecin(CPT)methacrylate and 5,10,15,20-tetraphenylporphyrin(TPP)-containing methacrylate monomers for complementary photodynamic-chemotherapy.The polyprodrug can self-assemble into polymeric micelles in aqueous solution with the suitable size and high stability.After intravenous injection,the polyprodrug micelles show tumor accumulation.Followed by light irradiation(650 nm)at tumor sites,TPP moieties induce singlet oxygen(1O2)production in the oxygen-rich area to exert PDT and cause transformation of the oxygen-rich areas into hypoxia.Simultaneously,in the hypoxic areas,the hypoxia-responsive polyprodrugs can be activated to release free CPT due to the cleavage of nitroimidazole linkages.The polyprodrug micelles with the segments for PDT and hypoxia-activable CPT efficiently suppress the growth of HeLa tumors.The well-defined polyprodrug amphiphiles offer an effective strategy to overcome the disadvantages of single treatment of PDT or hypoxia-responsive prodrugs for complementary photodynamic-chemotherapy of cancers.2nd Chapter:Due to the hypoxia microenvironment in solid tumors and the constant oxygen consumption of conventional PDT,PDT is low-efficiency inside solid tumors and usually requires combination with other therapeutic modalities for better therapeutic efficacy.In this chapter,we design and synthesize a new photosensitized molecule PDI-Dmani-S,which exhibits the properties of type I photosensitizers and can efficiently produce ROS even in the absence of oxygen.In addition,The absorption range of the photosensitizer is in the window of red light,which facilitates deep penetration in the tumor tissue.The photosensitizer molecule contains two amino groups at both sides,which is favorable for further modification or application to enhance its delivery ability in vivo.Covalent organic framework PTBCOF with the uniform size and high stability was obtained by reacting with meso-tetrakis(4-formylphenyl)porphyrin(p-Por-CHO).PTBCOF has high-efficiency production of singlet oxygen(1O2)and superoxide radicals(O2·-),which could produce O2·-efficiently under anaerobic conditions.By intravenous administration,PTBCOF can accumulate in tumor tissues through prolonged circulation and enhanced penetration and retention(EPR)effects.Under light irradiation,PTBCOF first consumes oxygen to produce 1O2 and O2·-for the cancer cells killing.With the gradual depletion of oxygen,PTBCOF could still rely on PDI-Dmani-S photosensitizer in the PTBCOF to produce O2·-and further kill cancer cells,thus effectively overcoming the defect of severe oxygen dependence in traditional photodynamic therapy.This strategy realized the coordination and complementary effect of type Ⅰ/Ⅱ photodynamic therapy and achieved an excellent antitumor effect in the hypoxic tumor microenvironment.3rd Chapter:Stimulator of interferon genes(STING)activation by STING agonists has been recognized as one of the potent and promising immunotherapy strategies.However,the immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy.In this chapter,we present polymeric metal-organic framework(PMOF)nanoparticles(NPs)for the combination of photodynamic therapy(PDT)and enhanced STING activation to improve the immunotherapeutic efficacy.The PMOF NPs with poly(ethylene glycol)(PEG)shells were obtained via coordination between the block copolymer ligand PEG-b-PABDA consisting of 1,4-bezenedicarboxylic acid-bearing polyacrylamide(PABDA),meso-tetra(carboxyphenyl)porphyrin(TCPP),thioketal diacetic acid,and ZrOCl2.Subsequently,the STING agonist SR-717 was loaded into the porous structure of PMOF to obtain SR@PMOF NPs which show excellent stability under the physiological conditions.After intravenous injection and tumor accumulation,light irradiation on the tumor sites results in efficient single oxygen(1O2)production from TCPP and cellular apoptosis to release fragmented DNA and tumor-associated antigens.Simultaneously,thioketal bonds can be broken by 1O2 to destroy the PMOF structure and rapidly release SR717.SR-717 and PDT synergistically enhance the antitumor immunity via combination photodynamic-immunotherapy due to reversal of the immunosuppressive tumor microenvironment and enhanced endogenous STING activation,which can suppress the growth of the primary and distant tumors efficiently.The oxidation-responsive SR@PMOF NPs represent a promising delivery system of STING agonists and efficient PDT NPs for simultaneous suppression of the primary and metastatic tumors via the rational combination of PDT and enhanced STING activation.