3 years ago

Traceable Nanoparticles with Spatiotemporally Controlled Release Ability for Synergistic Glioblastoma Multiforme Treatment

Traceable Nanoparticles with Spatiotemporally Controlled Release Ability for Synergistic Glioblastoma Multiforme Treatment
Yuanjie Shi, Xin Zhang, Yanhui Li, Zuobing Xiao, Yan Li, Zhiguo Lu
Doxorubicin (DOX), one of the most widely used clinical antineoplastics, has ineffective therapeutic efficacy on glioblastoma multiforme (GBM) with extremely short survival time due to many obstacles such as blood–brain barrier (BBB), tumor angiogenesis, and glioblastoma stem cells (GSCs). To overcome, biocompatible nanoparticles named CARD-B6 loading three clinical drugs are developed. Unlike other nanomedicines, CARD-B6, with the ability of spatiotemporally controlled release, maximize the effectiveness of DOX. (1) After CARD-B6 cross the BBB via B6, combretastatin A4 that is first released via protonation of poly (β-amino ester) specifically destroys angiogenesis to facilitate the interaction between GBM and CARD-B6. (2) Internalized into glioblastoma cells later, DOX is released via the breakage of amido bond to induce apoptosis, which is facilitated by the simultaneously released all-trans retinoic acid (ATRA). (3) After endocytosis into GSCs, the rapidly released ATRA induces the GSCs differentiation and downregulates the survival pathways, which enhances the sensitivity of GSCs to the subsequently released DOX. This synergistic antitumor effect significantly extends survival time of GBM mouse model. CARD-B6 are traced by superparamagnetic iron oxide nanocubes with high r2 relaxivity for magnetic resonance imaging. Therefore, the traceable CARD-B6 with spatiotemporally controlled release ability are emerging as a powerful platform for GBM treatment. CARD-B6 with spatiotemporally controlled release ability are successfully fabricated. CARD-B6 deliver CA4, ATRA, and Doxorubicin (DOX) to their corresponding active sites sequentially after across blood–brain barrier. The nanoparticles overcome the barriers of DOX for glioblastoma multiforme (GBM) therapy and significantly enhance the therapeutic efficacy of DOX with extended survival time, holding great potential for GBM therapy.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/adfm.201703967

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