Tumor-Acidity and Bioorthogonal Chemistry-Mediated On-Site Size Transformation Clustered Nanosystem to Overcome Hypoxic Resistance and Enhance Chemoimmunotherapy

Abstract

Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly­(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention. Subsequently, another tumor-acidity responsive group of the maleic acid amide with a slow response rate was cleaved allowing the aggregates to slowly dissociate into ultrasmall nanoparticles with better tumor penetration ability for the delivery of doxorubicin (DOX) and nitric oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced DOX resistance and boost the antitumor immune response through a reprogrammed tumor immune microenvironment. This tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem not only helps to counteract a hypoxia-induced chemoresistance and enhance antitumor immune responses but also provides a general drug delivery strategy for enhanced tumor accumulation and penetration.

Bacteria-driven hypoxia targeting delivery of chemotherapeutic drug proving outcome of breast cancer

“…To measure cellular uptake of the NPs, 4T1 cells were seeded in 6-well plates at the density of 2 × 10 5 cells/mL and incubated with normal saline (NS), free DOX or DOX-NPs for 2 h. The cells were then stained with DAPI for 5–10 min, washed thrice with PBS, and imaged by a fluorescence microscope (OLYMPUS, IX73, Japan). The fluorescence intensity of the internalized DOX was quantified by flow cytometry (BD FACSVerse, Piscataway, NJ) [ 52 ]. For the cytotoxicity assay, 4T1 cells were seeded into 96-well plates and treated with DOX, DOX-NPs or Bif@DOX-NPs for 24 h, and the MTT solution was then added to each well, after incubating the cells for another 4 h, 100 μL dimethyl sulfoxide was added to each well, and the OD was measured.…”

Recent advances in anti-multidrug resistance for nano-drug delivery system

“…The RSNO were conjugated with poly(thlene glycol)-block-poly(propylene sulfide) amphiphilic copolymer for encapsulating DOX, which was unable to respectively release DOX and NO by oxidative-reductive conversion (Wu et al., 2020 ). Similarly, NO donor and DOX were conjugated to poly(amidoamine) (PAMAM) via acid-cleavable cross-link and then were further masked by modified PEG, which could release NO to reverse hypoxia-induced drug resistance (Wang et al., 2022 ). The NO-responsive liposome was designed to NIR-trigger drug release and inhibits P-gp in combination with Au-nanorod-embedded CuS shell, allowing NO and DOX release in drug-resistant tumor cells to kill MDR cancer cells (Wang et al., 2019a ).…”

Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy

“…To balance the favorable sizes for blood circulation in the body, tumor accumulation, and tumor penetration, size-switchable nanomedicines have emerged as a tailor-made remedy for tumor-penetrating therapy. − They typically possess suitable initial physicochemical properties (diameters ranging from 100 to 200 nm) for long blood circulation and optimal tumor accumulation and sharply switch to ultrasmall nanoparticles (ca. 10 nm) at the tumor site for improved interstitial diffusion in response to various endogenous or external stimuli. ,− However, often the resulting ultrasmall nanoparticles remain inaccessible to deep-seated tumor cells owing to the compact extracellular matrix and elevated interstitial pressure, consequently dramatically reducing diffusion . Transcytosis, which utilizes the intrinsic pathway of deep-seated tumor cells to intake nutrition, is a burgeoning strategy to promote transcellular delivery of nanomedicines .…”