Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation

Abstract

Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…(g) Immunofluorescence images of expressed HIF-1αin different groups. Reprinted with permission under a Creative Commons CC BY License from ref . Copyright (2022) BioMed Central.…”

“…298 Besides, Liu et al constructed a drug delivery nanoplatform by encapsulating BEZ235 and photosensitizer Ce6 in 4-(2aminoethyl) benzenesulfonamide and PEG-NH 2 modified hollow polydopamine to reduce tumor acidification, block the PI3K/mTOR signal, and slow down HIF-1α-dependent tumor adaptation to low O 2 for phototherapy (Figure 8f). 294 In detail, carbonic anhydrase IX inhibitor, 4-(2-aminoethyl) benzenesulfonamide, which can cause intracellular acidification, has shown excellent antitumor effects in some research. The BEZ235 can be released in an acid microenvironment to inhibit the PI3K/AKT/mTOR pathway and suppress HIF-1α expression, thus resisting HIF-1α-dependent tumor hypoxia adaptation (Figure 8g).…”

Targeting hypoxia-inducible factors for breast cancer therapy: A narrative review

“…A polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer (Soluplus) encapsulated BA micelle (Soluplus-BA) was fabricated and results showed that Soluplus-BA micelles increased the inhibitory effect of BA on the angiogenesis by regulating the HIF-1/VEGF-FAK signaling pathway in breast cancer MDA-MB-231 cells ( Qi et al, 2021 ). Recently a photodynamic therapy based on conjugated PNPs for BC has been reported ( Liu et al, 2022 ). Ying Zhang et al (2022) synthesized photochemical-responsive nanoparticle by incorporating DOX, curcumin (CUR), and perfluorooctyl bromide (PFOB) into poly (lactic-co-glycolic acid) (PLGA) via double emulsification (DOX-CUR-PFOB-PLGA).…”

“…A drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4-(2-aminoethyl) benzene sulfonamide (ABS) was designed to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The study showed that the H-APBC could produce ROS upon light irradiation and release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation ( Liu et al, 2022 ). Photodynamic therapy (PDT) has become an emerging area of modern medicine.…”

Diagnosing Orthotopic Lung Tumor Using a NTR-Activatable Near-Infrared Fluorescent Probe by Tracheal Inhalation

“…Carbonic anhydrase IX (CAIX) is a transmembrane protein that is triggered by the high expression of hypoxia-inducing factor 1 (HIF-1) in most tumor tissues at hypoxic sites. − Its main function is to catalyze the hydration of CO 2 to generate hydrogen protons and bicarbonate, thereby regulating the pH homeostasis within and without the cell. − Once CAIX overexpression leads to a slightly TME change, it can combine with hypoxic conditions to promote tumor growth and angiogenesis, facilitate tumor metastasis, and interfere with the expression of genes and related proteins. ,− …”