Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 13, Issue 48, Pages 56858-56872Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c16351
Keywords
inhaled chemotherapy; paclitaxel dimer; glutathione; reactive oxygen species; disulfide bonds; pulmonary toxicity
Funding
- National Natural Science Foundation of China [81573380, 81850410554, 82050410448]
- Overseas Expertise Introduction Project for Discipline Innovation (111Project) [D20029]
- Guiding Project for Science and Technology of Liaoning Province [2019-ZD-0448]
- Ministry of Education Chunhui Program
- Program for Talents and Team of Science and Technology in University of Yunnan Province [202105AE160010]
- China Postdoctoral Science Foundation, China [2021MD703857]
- [XLYC2002061]
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This study introduced redox-responsive PTX dimeric nanoparticles for pulmonary delivery to achieve effective therapeutic outcomes against metastatic lung cancer with reduced systemic and local toxicities. These nanoparticles exhibited optimal drug release behavior, excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. In a mouse model of metastatic lung cancer, intratracheally delivered PTX dimeric nanoparticles showed stronger anticancer potential with reduced systemic toxicity compared to traditional Taxol intravenous injection.
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., alpha-PTX-SS-PTX, beta-PTX-SS-PTX, and gamma-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, beta-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 (beta-PTX-CC-PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered beta-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.
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