Stephan MT, Moon JJ, Um SH et al.Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med 16:1035-1041

Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nature medicine (Impact Factor: 27.36). 09/2010; 16(9):1035-41. DOI: 10.1038/nm.2198
Source: PubMed


A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

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    • "They will be recognized by overexpressed molecular patterns at the tissues/cells intended to target, facilitating NP recognition and subsequent receptor-mediated endocytosis (Figure 6) (Cheng et al., 2007; Kumar et al., 2009; Danhier et al., 2010; Aslan et al., 2013; Nicolas et al., 2013; Wang et al., 2013a; Gao et al., 2014). Surface modifications represent an outstanding tool for cell targeting allowing a specific contact of nanoparticulate systems with critical immune cells, as evidenced in Stephan et al. (2010). For example, the ligand DEC-205 is highly expressed by CD8+DCs, cells particularly efficient at " cross-presenting " exogenous antigens on MHCI, constituting a highly relevant pathway for the development of a cytolytic immune response. "
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    • "T-cell-bound particles provided pseudo-autocrine drug delivery to the transferred cells that greatly increased the effective potency of adjuvant drugs while simultaneously minimizing systemic exposure to these potent supporting signals. This approach allowed autocrine delivery of interleukin cytokines that dramatically enhanced the efficacy of ACT T-cells in a metastatic melanoma model [15] and the delivery of immunosuppression-blocking drugs that enhanced expansion of T-cells within large established tumors in a prostate cancer model [16]. A limitation of the pharmacyte approach is the one-time nature of the intervention: ACT T-cells can only be loaded once with a cargo of adjuvant drug prior to transfer, and the duration of stimulation is inherently limited by expansion of the cell population in vivo, since cell-bound particles are diluted with each cell division. "
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    • "Especially in the area of signaling, significant progress has been made over the past few years. Biomaterials that slowly deliver proteins,[25] drugs,[26] plasmids,[27] viruses,[27] and microRNAs[28] to surrounding tissue are currently available. "
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