期刊
ADVANCED FUNCTIONAL MATERIALS
卷 30, 期 16, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201908788
关键词
cancer; chemotherapy; immunotherapy; nitric oxide; paclitaxel
类别
资金
- US National Institutes of Health [R01CA207619, S10OD016264, T32EB006343]
- American Heart Association
- US Department of Defense [CA150523]
Despite the approval of oncolytic virus (OV) therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, reported is a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide-incorporated polymerized beta-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of OV. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell (DC) activation, and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of DCs systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8(+) T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo- and immunotherapeutic synergies of PTX and nitric oxide and suggests the potential for virus-free nanoformulations to mimic the therapeutic action and benefits of OVs.
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