4 years ago

Microneedle-Assisted, DC-Targeted Codelivery of pTRP-2 and Adjuvant of Paclitaxel for Transcutaneous Immunotherapy

Microneedle-Assisted, DC-Targeted Codelivery of pTRP-2 and Adjuvant of Paclitaxel for Transcutaneous Immunotherapy
Yongzhuo Huang, Beihua Xu, Ying Hu, Jiaojiao Xu, Yunxu Yang, Jin Tao
This work aims at developing an immunotherapeutic strategy to deliver a cancer DNA vaccine targeting dendritic cells (DCs), to trigger their maturation and antitumor function, and reduce immune escape using a polymeric nanocomplex of paclitaxel (PTX)-encapsulated sulfobutylether-β-cyclodextrin (SBE)/mannosylated N,N,N-trimethylchitosan (mTMC)/DNA. To enhance DC-targeting and revoke immunosuppression is the major challenge for eliciting effective antitumor immunity. This codelivery system is characterized by using low-dose PTX as an adjuvant that is included inside SBE, and the PTX/SBE further serves as an anionic crosslinker to self-assemble with the cationic mTMC/DNA polyplexes. This system is used in combination with a microneedle for transcutaneous vaccination. Once penetrating into the epidermis, the mannosylated nanocomplexes would preferentially deliver the pTRP-2 DNA vaccine inside the DCs. Phenotypic maturation is demonstrated by the increased expression of costimulatory molecules of CD80 and CD86, and the elevated secretion of IL-12p70. The mixed leucocyte reactions reveal that the PTX/SBE-mTMC/DNA nanocomplexes enhance the proliferation of CD4+ and CD8+ T cells, and inhibit the generation of immune-suppressive FoxP3+ T cells. The system shows high antitumor efficacy in vivo. The PTX/SBE-mTMC/DNA nanocomplexes for DC-targeted codelivery of DNA vaccine and adjuvant PTX yield synergistic effects on the DC maturation and its presenting functions, thus increasing immune stimulation and reducing immune escape. Paclitaxel-based therapy possesses dose-dependent Yin-and-Yang nature. Normal dose impairs the immune system, while low dose displays the adjuvant function for stimulating immune responses and promoting the maturation of dendritic cells (DCs). A polymeric nanoassembly system is proposed for microneedle-assisted codelivery of a pTRP-2 vaccine targeting the epidermis DCs and the imunomodulator low-dose paclitaxel for enhanced cancer immunotherapy.

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

DOI: 10.1002/smll.201700666

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