Therapeutic cell engineering with surface-conjugated synthetic nanoparticles.

Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nature medicine (Impact Factor: 28.05). 09/2010; 16(9):1035-41. DOI: 10.1038/nm.2198
Source: PubMed

ABSTRACT 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.

  • Source
    International Journal of Nanomedicine 12/2014; 10:97-113. · 4.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Targeted delivery of drugs and imaging agents to inflamed tissues, as in the cases of cancer, Alzheimer's disease, Parkinson's disease, and arthritis, represents one of the major challenges in drug delivery. Monocytes possess a unique ability to target and penetrate into sites of inflammation. Here, we describe a broad approach to take advantage of the natural ability of monocytes to target and deliver flat polymeric particles ("Cellular Backpacks") to inflamed tissues. Cellular backpacks attach strongly to the surface of monocytes but do not undergo phagocytosis due to backpack's size, disk-like shape and flexibility. Following attachment of backpacks, monocytes retain important cellular functions including transmigration through and endothelial monolayer and differentiation into macrophages. In two separate in vivo inflammation models, backpack-laden monocytes exhibit increased targeting to inflamed tissues. Cellular backpacks, and their abilities to attach to monocytes without impairing monocyte functions and 'hitchhike' to a variety of inflamed tissues, offer a new platform for both cell-mediated therapies and broad targeting of inflamed tissues. Copyright © 2014. Published by Elsevier B.V.
    Journal of Controlled Release 12/2014; · 7.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Advances in nanotechnology have resulted in the introduction of new materials for therapeutic and diagnostic purposes. In particular, DNA and RNA are viewed as representative and generic nano-blocks because of their physiochemical characteristics of specificity and nanoscopic-level accuracy. In addition, the intrinsic biocompatibility of DNA and RNA and their immune stimulation effects make these molecules ideal candidates for the rational design of novel bio-drug molecules. Recently, we reported novel RNA-DNA hybrid stem-loop structures that target and are endocytosed by LNCaP prostate cancer cells with high specificity. To effectively ligate the DNA and RNA modules in this research, we thoroughly evaluated and optimized several ligation parameters, and observed that we could enhance the ligation efficacy by changing the overhang sequences. A change in sequence information (GCAT) resulted in a 4-fold increase in ligation efficiency in comparison with other ligation factors. To determine the in vitro cellular targeting ability of the nanostructures, RNA-DNA hybrid constructs were complexed with gold nanorods (AuNRs), and the ability of these nanorods to target prostate cancer cells was highest at a 2:10 molar ratio of LNCaP cancer-specific looped A10 RNA to stem-DNA. Furthermore, doxorubicin (Dox) as a representative anti-prostate cancer therapeutic was loaded into the DNA-RNA hybrid nanostructures. Our results indicate that RNA-DNA hybrid constructs are effective anti-prostate cancer drug delivery platforms and can be employed for both discovery and delivery.
    Biomaterials Science. 01/2014; 2(1):76.

Full-text (2 Sources)

Available from
Jun 3, 2014