Synthesis And Investigation Of Tumor Microenvironment Regulated Nanomedicine For Enhanced Photodynamic Therapy

Currently,the strategy of clinical cancer treatment is surgery followed by chemotherapy.However,the therapeutic efficacy is greatly reduced owing to limited chemotherapeutic drug accumulation in the lesion site.Thus,the repeated treatment result in multidrug resistance（MDR）generation and serious adverse effects,and leading to tumor recurrence,metastasis and even death.As a physical selective and minimal invasive cancer treatment mode,photodynamic therapy（PDT）has been favored by scientists.Nevertheless,the actual clinical efficacy of PDT are limited by complicated tumor microenvironment and the bioavailability of drugs restricted by various biological barriers.The limitation of antitumor immune response caused by hypoxic tumor microenvironment may promote the immune system to accelerate tumorigenesis and tumor deterioration.Thus,designing excellent performance of photosensitizer and constructing a targeted drug delivery system is to aggrandize retention and accumulation of drug in tumor sites.Meanwhile,modulating tumor microenvironment to magnify PDT sensitization for implementing tumor ablation under the condition of fewer doses and lower therapeutic frequency.The main designing thought,research contents and experimental results of this paper are summarized as follows:（1）Based on the hypoxic tumor microenvironment,a catalase-based multifunctional folate-targeted liposomal nanomedicine（FA-L@MD@CAT）encapsulating lysosomal anchored near infrared（NIR）photosensitizer（MBDP）and doxorubicin hydrochloride（Dox·HCl）was designed and constructed.In vivo and in vitro experiments illustrated that FA-L@MD@CAT could accomplish accuracy delivery and tremendous intratumoral retention in lesion sites by specific recognition of folate receptor upregulated breast cancer,and its targeting efficiency increased by 11.4 times.Moreover,FA-L@MD@CAT could catalyze overexpressed H₂O₂ into O₂ to improve tumor oxygenation,and then amplify PDT-induced ¹O₂ yield and reverse immunosuppressive tumor microenvironment for realizing enhanced chemotherapy-PDT-immunotherapy synergistic anti-tumor efficacy.The tumor inhibition rate was up to 96.7%.（2）Based on the GSH-overexpressed tumor microenvironment,containing maleimide and high-efficiency NIR photosensitizer（NBS）was designed and synthesized,which self-assembled into a CD44 specific targeted nanomedicine AM-L@NBS.In vivo and in vitro studies have clarified that AM-L@NBS could exhaust intratumoral overexpressed GSH for upregulated ¹O₂ and O₂^·-level,and its IC₅₀ value（16.4 n M）revealed 315-fold enhancement compared with commercial Ce6.Furthermore,AM-L@NBS exhibited significant retention and penetration depth in CD44 overexpressed breast cancer,and the sharp reactive oxygen generation triggered apoptosis and ultimately accomplished tumor elimination.（3）To overcome MDR tumor,an ingenious multifunctional nanomaterial L@BP was fabricated by loading mitochondria-anchored photosensitizer（Cy-Br）and paclitaxel（PTX）.At the cellular level,L@BP could surmount endosomal traps,released photosensitizer could implement high mitochondrial retention and dramatically reinforce the synergistic therapy for MDR cancer.PDT-induced in situ mitochondrial dysfunction resulted in reduced P-gp transport capacity owing to the downregulated ATP level,which aggrandized intracellular drug concentration for amplifying therapeutic efficacy on PTX-resistant lung cancer cells.The MDR tumor inhibition rate was 86.4%.