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“Navigate-dock-activate” anti-tumor strategy: Tumor micromilieu charge-switchable, hierarchically activated nanoplatform with ultrarapid tumor-tropic accumulation for trackable photothermal/chemotherapy
The delivery of therapeutics into tumors remains a challenge in nanoparticle-mediated drug delivery. However, effective therapies such as photothermal therapy (PTT) are limited by quick systemic clearance and non-specific biodistribution. Anti-tumor strategies tailored to accommodate both tumor accu...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525992/ https://www.ncbi.nlm.nih.gov/pubmed/31131050 http://dx.doi.org/10.7150/thno.33280 |
Sumario: | The delivery of therapeutics into tumors remains a challenge in nanoparticle-mediated drug delivery. However, effective therapies such as photothermal therapy (PTT) are limited by quick systemic clearance and non-specific biodistribution. Anti-tumor strategies tailored to accommodate both tumor accumulation/retention and cellular internalization under a single platform would be a promising strategy. This work demonstrates a hierarchical activating strategy that would exhibit enhanced circulation and rapid tumor-tropism as well as facilitate tumor penetration, followed by tumor-specific drug release to realize trackable photothermal/chemotherapy. Methods: We engineered a lithocholic acid-conjugated disulfide-linked polyethyleneimine micelle (LAPMi) loaded with paclitaxel (LAPMi-PTX, L), followed by the electrostatic adsorption of indocyanine green (ICG, I) on LAPMI-PTX and subsequently coated them with thermosensitive DPPC and DSPE-PEG-NH(2) lipids (L), producing Lipid/ICG/LAPMi-PTX (LIL-PTX) nanoparticles (NPs). The characteristics of NPs, including physicochemical characterization, photothermal & pH responsiveness, cell uptake, tumor spheroid penetration, anti-tumor efficacy and hierarchical activation of LIL-PTX NPs were investigated in vitro and in vivo by using CT26 cell line. The anti-metastatic potential of LIL-PTX NPs were demonstrated using 4T1 orthotopic tumor model. Results: The NPs synthesized possessed charge switchability in the mildly acidic pH, and were laser- and pH-responsive. Dual stimuli-responsive nature of LIL-PTX NPs improved the disposition of therapeutics to the tumor, reflected by enhanced intracellular uptake, tumor spheroid penetration and in vitro cytotoxicity studies. LIL-PTX NPs readily switched its surface charge from neutral to positive upon reaching the tumor milieu, thus resulting in rapid tumor tropism and accumulation. Under near-infrared laser irradiation, the thermosensitive lipids on LIL-PTX NPs were deshielded, and the tumor-penetrating LAPMi-PTX was subsequently exposed to the tumor milieu, thus resulting in enhanced intracellular internalization. Next, LAPMi-PTX evaded the endo-lysosomes, thereby releasing the PTX through the degradation of LAPMi mediated by intracellular GSH in the tumor. LIL-PTX NPs significantly improved the therapy by eradicating primary tumors completely and suppressing their subsequent lung metastasis. Conclusion: The improved therapeutic index is due to enhanced passive targeting by rapid tumor-tropic accumulation and tumor penetration by laser-driven exposure of LAPMi, thereby improving the therapeutic delivery for image-guided photothermal/chemotherapy. |
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