TY - JOUR
T1 - Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer
AU - Tian, Xidong
AU - Bera, Hriday
AU - Guo, Xiong
AU - Xu, Ruizhao
AU - Sun, Jin
AU - He, Zhonggui
AU - Cun, Dongmei
AU - Yang, Mingshi
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1021/acsami.1c16351
DO - 10.1021/acsami.1c16351
M3 - Journal article
C2 - 34806372
VL - 13
SP - 56858
EP - 56872
JO - ACS applied materials & interfaces
JF - ACS applied materials & interfaces
SN - 1944-8244
IS - 48
ER -