Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer

Abstract

Chemotherapeutics often failed to elicit optimal antitumor responses against lung cancer due to their limited exposure and accumulation in tumors. To achieve an effective therapeutic outcome of paclitaxel (PTX) against metastatic lung cancer with attenuated systemic and local toxicities, pulmonary delivery of redox-responsive PTX dimeric nanoparticles (NPs) was introduced. PTX dimers conjugated through variable lengths of diacid linkers containing disulfide bonds (−SS−) (i.e., α–PTX–SS–PTX, β–PTX–SS–PTX, and γ–PTX–SS–PTX) were initially synthesized and were subsequently self-assembled into uniform nanosized particles in the presence of vitamin E TPGS with high drug loading capacity (DE > 97%). Among various redox-sensitive scaffolds, β–PTX–SS–PTX NPs exhibited an optimal reactive oxygen species/glutathione-responsive drug release behavior, causing a lower local toxicity profile of PTX in the lungs. The scaffolds also demonstrated excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. Further, they depicted an improved lung retention as compared to the control nanovesicles (β–PTX–CC–PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered β–PTX–SS–PTX NPs exhibited a stronger anticancer potential with reduced systemic toxicity as compared to Taxol intravenous injection containing an equivalent PTX dose. The PTX dimeric NPs could also dramatically reduce the local toxicity relative to Taxol following their pulmonary delivery. Thus, this study presents redox-responsive PTX dimeric NPs as a promising nanomedicine for improved therapeutic efficacy against metastatic lung cancer.

An activatable, carrier-free, triple-combination nanomedicine for ALK/EGFR-mutant non-small cell lung cancer highly permeable targeted chemotherapy

“…According to previous studies, [44][45][46] the CA4-SS-Cer NP nanoassemblies were prepared using a one-step nanoprecipitation method. The structure of CA4-SS-Cer allows for its aggregation into uniform-sized NPs in deionized water.…”

Engineering Transferrin-Decorated Pullulan-Based Prodrug Nanoparticles for Redox Responsive Paclitaxel Delivery to Metastatic Lung Cancer Cells

“…Upon exposure to DTT media, the disulfide pendants (−SS−) of the prodrug NPs were degraded, yielding a hydrophilic thiol intermediate (PTX−SH). This could easily hydrolyze the ester bonds located at the β-position (Figure 5A), 4 resulting in an accelerated PTX release profile (∼75− 86% drug release within 24 h) with greater mean dissolution time (MDT) and dissolution efficiency (DE) values (Table 2). The prodrug NPs endowed with distinct redox-triggered drug release properties might be promising for the targeted drug delivery to the lung tumor microenvironments bearing amplified levels of GSH 45 .…”

“…DAPI, a blue-fluorescent DNA stain, was employed to visualize the cell nucleus. 4 The green fluorescent dots of coumarin 6 were detected within the cell cytoplasm following treatment with various NPs, and the fluorescence intensity was augmented with increasing incubation time from 1 to 4 h (Figure S5A). This indicated that NPs were efficiently internalized into the lung cancer cells and their cellular uptake processes were time-dependent.…”

Dual-responsive disassembly of core-shell nanoparticles with self-supplied H2O2 and autocatalytic Fenton reaction for enhanced chemodynamic therapy

“…After 4 days of intravenous injection of B16F10 cells, mice were treated with PBS, AuNPs, and Au@MPN via intratracheal instillation, which allowed the solutions to distribute throughout the lungs in a physiological manner with high reproducibility, accuracy, and efficacy (Fig. 7A) 37 . As shown in Fig.…”