Dual pH/redox-responsive size-switchable polymeric nano-carrier system for tumor microenvironment DTX release.

Innovation chemotherapeutic nano drug delivery systems (NDDSs) with various pharmacological achievement have become one of the hopeful therapeutic strategies in cancer therapy. This study focused on low pH, and high levels of glutathione (GSH) as two prominent characteristics of the tumor microenvironment (TME) to design a novel TME-targeted pH/redox dual-responsive P (AMA-co-DMAEMA)-b-PCL-SS-PCL-b-P (AMA-co-DMAEMA) nanoparticles (NPs) for deep tumor penetration and targeted anti-tumor therapy. The positively charged NPs exhibit strong electrostatic interactions with negatively charged cell membranes, significantly enhancing cellular uptake. Moreover, these NPs possess the unique size-shrinkable property, transitioning from 98.24 ± 27.78 to 45.56 ± 20.62 nm within the TME. This remarkable size change fosters an impressive uptake of approximately 100% by MDA-MB-231 cells within just 30 min, thereby greatly improving drug delivery efficiency. This size switchability enables passive targeting through the enhanced permeability and retention (EPR) effect, facilitating deep penetration into tumors. The NPs also demonstrate improved pH/redox-triggered drug release (∼70% at 24 h) within the TME and exhibit no toxicity in cell viability test. The cell cycle results of treated cells with docetaxel (DTX)-loaded NPs revealed G2/M (84.6 ± 1.16%) arrest. The DTX-loaded NPs showed more apoptosis (62.6 ± 3.7%) than the free DTX (51.8 ± 3.2%) in treated cells. The western blot and RT-PCR assays revealed that apoptotic genes and proteins expression of treated cells were significantly upregulated with the DTX-loaded NPs vs. the free DTX (Pvalue<.001). In conclusion, these findings suggest that this novel-engineered NPs holds promise as a TME-targeted NDDS.

Dual pH/redox-responsive hyperbranched polymeric nanocarriers with TME-trigger size shrinkage and charge reversible ability for amplified chemotherapy of breast cancer.

A novel pH/redox-responsive hyperbranched MeO-PEG-b-(NIPAAm-co-PBAE) nanoparticles (NPs) were designed with size shrinkage and charge-reversible potential for targeted delivery of docetaxel (DTX) to MDA-MB-231 cell lines. In the tumor microenvironment (TME), amine protonation induces charge reversal and disulfide bond cleavage under high TME GSH concentration causing size shrinkage, improved deep tumor penetration, and active targeting of the therapeutic agents. These nano drug delivery systems (NDDSs) significantly promoted cancer cell uptake (~ 100% at 0.5 h), facilitating site-specific delivery and deep tumor penetration. The MTT assay revealed significantly higher cytotoxicity (P value < 0.0001) for DTX-loaded NPs compared to free DTX. Cell cycle analysis revealed G2/M (58.3 ± 2.1%) and S (21.5 ± 1.3%) arrest for DTX-loaded NPs, while free DTX caused G2/M (67.9 ± 1.1%) and sub-G1 (10.3 ± 0.8%) arrest. DTX-loaded NPs induced higher apoptosis (P value < 0.001) in MDA-MB-231 cells (71.5 ± 2.8%) compared to free DTX (42.3 ± 3.1%). Western blotting and RT-PCR assays confirmed significant up-regulation of protein levels and apoptotic genes by DTX-loaded NPs compared to free DTX. In conclusion, TME-responsive charge reversal and size-shrinkable smart NDDSs designed based on low pH, and high glutathione (GSH), offer more effective site-specific delivery of therapeutic agents to tumors.

pH/redox responsive size-switchable intelligent nanovehicle for tumor microenvironment targeted DOX release.

Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific targeted delivery. In this study, (PAA-b-PCL-S-S-PCL-b-PAA) copolymeric nanoparticles (NPs) with size-switchable ability and dual pH/redox-triggered drug release behavior were designed to significantly promote cancer uptake (cell internalization of around 100% at 30 min) and site-specific targeted doxorubicin (DOX) delivery in MDA-MB-231 tumor cells. NPs surface charge was shifted from - 17.8 to - 2.4 and their size shrunk from 170.3 to 93 nm in TME. The cell cycle results showed that DOX-loaded NPs showed G2/M (68%) arrest, while free DOX showed sub-G1 arrest (22%). Apoptosis tests confirmed that the cells treated with DOX-loaded NPs showed a higher amount of apoptosis (71.6%) than the free DOX (49.8%). Western blot and RT-PCR assays revealed that the apoptotic genes and protein levels were significantly upregulated using the DOX-loaded NPs vs. the free DOX (Pvalue < 0.001). In conclusion, dual pH/redox-responsive and size-switchable DOX-loaded NPs developed here showed outstanding anti-tumoral features compared with free DOX that might present a prospective platform for tumor site-specific accumulation and drug release that suggest further in vivo research.