Super-pH-Sensitive Mesoporous Silica Nanoparticle-Based Drug Delivery System for Effective Combination Cancer Therapy

Abstract

A multifunctional nanoplatform based on mesoporous silica nanoparticles (MSNs) was developed for combinational tumor therapy. Doxorubicin (DOX) was chosen as an antitumor drug and loaded into mesopores of MSNs via physical absorption. Then, a tumor-targeted fusion peptide conjugated with 2,3-dimethylmaleic anhydride (DTCPP) and a therapeutic peptide conjugated with 2,3-dimethylmaleic anhydride (DTPP) were introduced to the surface of MSNs as super-pH-sensitive nanovalves through disulfide linkages. The BSA adsorption assay confirmed the charge-reversal property of MSN-ss-DTPP&DTCPP nanoparticles at slightly acidic condition (pH 6.8) and superior stability in physiological environment (pH 7.4). According to the drug release research, both glutathione (GSH) and acidic condition are required for the accelerated drug release from DOX@MSN-ss-DTPP&DTCPP nanoparticles. Moreover, in vitro studies demonstrated the significantly reinforced tumor cellular uptake efficiency and mitochondrial disruption ability of DOX@MSN-ss-DTPP&DTCPP nanoparticles in tumor environment, in which DOX@MSN-ss-DTPP&DTCPP nanoparticles exhibited the preferred cytotoxicity toward αvβ3-positive human cervical carcinoma (HeLa) cells. We believe that the multifunctional dual-stimuli-sensitive MSN could provide an effective strategy for combinational tumor therapy.

Anticancer Compounds Derived from Marine Diatoms

“…The DOX@MSN-ss-DTPP&DTCPP has demonstrated higher cytotoxicity against HeLa cells with the IC 50 of 1.4 µg/mL after 48 h treatment. The release of DOX and TPP peptide from DOX@MSN-ss-DTPP&DTCPP NPs can target the nucleus and mitochondria of HeLa cells at the same time, and exhibit stimulation of cell apoptosis [65]. (e) removal of TPP and TCPP peptides from DOX-loaded NPs that caused by GSH; (f) release of DOX into the nucleus, leading to DNA damage; (g) GSH-triggered TPP peptide release into the mitochondria, producing a special mitochondrial disorder (Reprinted from [65], with permission from American Chemical Society).…”

“…Using micro-fluidics methods under an external magnetic field, as shown in Figure 10, combined SiNPs loaded with drugs and magnetic nanowires, and encased in a polymeric matrix sensitive to pH, have been synthesized to target SW480 colon cancer cells. The SiNPs and magnetic nano-wires (BacNWs) bearing Curcumin (CUR) or 5-Flourouracil (5FU) by using physical-adsorption, have resulted in (e) removal of TPP and TCPP peptides from DOX-loaded NPs that caused by GSH; (f) release of DOX into the nucleus, leading to DNA damage; (g) GSH-triggered TPP peptide release into the mitochondria, producing a special mitochondrial disorder (Reprinted from [65], with permission from American Chemical Society).…”

Dual-responsive doxorubicin-loaded nanomicelles for enhanced cancer therapy

“…Tremendous efforts had been devoted to the development of stimuli-responsive tumor-targeted drug delivery systems to deal with aforementioned dilemma. On one hand, pH-dependent charge conversion strategy is utilized to construct polymeric drug, which maintains their stealth features during circulation and then undergoes a charge reversal process for achieving enhanced tumor cells' internalization once exposed to tumor relative acidic environment [15][16][17][18]. On the other hand, polymeric drug with ROS generation capability will be an effective approach to copying with insufficient ROS concentration for activating the complete drug release [13][14][15]19].…”

Dual-responsive doxorubicin-loaded nanomicelles for enhanced cancer therapy

“…Tremendous efforts had been devoted to the development of stimuli-responsive tumor-targeted drug delivery systems to deal with aforementioned dilemma. On one hand, pH-dependent charge conversion strategy is utilized to construct polymeric drug, which maintains their stealth features during circulation and then undergoes a charge reversal process for achieving enhanced tumor cells' internalization once exposed to tumor relative acidic environment [15][16][17][18] . On the other hand, polymeric drug with ROS generation capability will be an effective approach to copying with insu cient ROS concentration for activating the complete drug release [13][14][15]19] .…”