Tumor Acidic Microenvironment Targeted Drug Delivery Based on pHLIP-Modified Mesoporous Organosilica Nanoparticles

Abstract

Enhancing the tumor-targeting delivery of chemotherapeutic drugs is important yet challenging for improving therapeutic efficacy and reducing the side effects. Here, we first construct a drug delivery system for targeting tumor acidic microenvironment by modification of pH (low) insertion peptide (pHLIP) on mesoporous organosilica nanoparticles (MONs). The MONs has thioether-bridged framework, uniform diameter (60 nm), good biocompatibility, and high doxorubicin (DOX) loading capacity (334 mg/g). The DOX loaded in the pHLIP modified MONs can be released responsive to glutathione and low pH circumstance, ensuring the chemotherapeutic drug exerts higher cytotoxic effects to cancer cells than normal cells because of high intracellular GSH of tumor cells and low pH of tumor microenvironment. Moreover, the engineered MONs exhibit higher cellular uptake in pH 6.5 medium by MDA-MB-231 and MCF-7 cells than the particles decorated with polyethylene glycol (PEG). Importantly, the pHLIP-mosaic MONs with DOX displays better cytotoxic effects against the breast cancer cells in pH 6.5 medium than pH 7.4 medium. The in vivo experiments demonstrate that the pHLIP modified MONs are accumulated in the orthotopic breast cancer via targeting to acidic tumor microenvironment while no serious pathogenic effects was observed. After loading DOX, the pHLIP-modified MONs display better therapeutic effects than the control groups on the growth of MCF-7 breast cancers, showing promise for enhancing chemotherapy.

Disulfide‐Bridged Organosilica Frameworks: Designed, Synthesis, Redox‐Triggered Biodegradation, and Nanobiomedical Applications

“…Based on TEM analysis of the as‐prepared, air‐calcined, and N 2 ‐calcined products ( Figure ), the CTAB–BTEPTS organosilica nanospheres (size: 150 nm) showed a hydrocarbon‐rich core and a silica‐rich shell‐like nanostructure, while C 18 TMS–BTEPTS organosilica nanospheres (size: 150 nm) showed the reverse situation. Teng et al synthesized uniform MONs with disulfide‐bridged organosilica frameworks in the BTEPTS–TEOS–CTAB–NH 3 ·H 2 O–ethanol–water system at 35 °C with a molar ratio of 0.179 of BTEPTS/TEOS . The particle size could be tailored in the range of 90–290 nm by adjusting the CTAB concentration or the ethanol/water volume ratio.…”

“…For disulfide‐bridged yolk–shell MONs, higher GSH concentrations led to quicker DOX release due to GSH‐triggered breakage of disulfide bonds, which further destroyed the hydrophobic interaction between DOX and the framework. However, 24 h of treatment in PBS solution with 10 × 10 −3 m GSH just slightly changed the shape and caused indistinct edges, while more than 2 weeks resulted in the obvious breakdown of the yolk–shell structure .…”

“…Moreover, these MONs were found to exhibit low cytotoxicity, good blood hemocompatibility, and histocompatibility. Both MONs modified with anti‐Her2 affibody molecule for the specific recognition of Her2 expressed in tumor cells and MONs modified with acidic pH insertion peptide for targeting tumor acidic microenvironment exhibited enhanced cancer cell killing capacity in vitro and tumor inhibition in vivo in mice . In another example, CuS‐doped yolk–shell MONs showed complete tumor growth suppression without recurrence toward U87MG tumor‐bearing mice owing to mild hyperthermia‐improved chemotherapy .…”

“…Xu and co‐workers found significantly higher excretion of Si amounts via urine in the mice group treated with DOX‐embedded and disulfide‐bridged NPs, compared with conventional silica NPs . Most disulfide‐bridged NPs with and without modifications showed negligible indications of cytotoxicity, good hemocompatibility, and in vivo biocompatibility . Their degraded products were also found to have low cytotoxicity; however, the accurate characterizations of the degraded products are still urgently needed.…”

“…The in vitro and in vivo biosafety of the degraded products should also be given much more attention. Moreover, based on disulfide‐bridged silsesquioxane frameworks, various nanosystems were developed and exhibited efficient in vivo cancer diagnostic and/or therapeutic effect toward mice . In short, the rapid degradation rates (such as complete degradation within 2 days) can accelerate the release rate of loaded guest molecules and cause their complete release for better biological effects, also facilitating the quick excretion of degraded products, and improving the biosafety of the injected NPs.…”