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Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles.

ABSTRACT: Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.

SUBMITTER: Stephan MT

PROVIDER: S-EPMC3395588 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles.

Stephan Matthias T MT Stephan Sirkka B SB Bak Peter P Chen Jianzhu J Irvine Darrell J DJ

Biomaterials 20120515 23

Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We de ...[more]

PMID: 22594972

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Project description:Interaction of nanomaterials with the mammalian cells remains to be poorly understood at the molecular level. Here we report the first synthesis of hybrid nanomaterial termed phage mimetic nanorods (PMN’s) inspired from filamentous bacteriophage present in nature. We emulate filamentous bacteriophage structure by combining two separate nanoscale entities, one functionalized gold nanorods and the other is coat proteins isolated from filamentous bacteriophage obtained through landscape phage screening. Utilizing biochemical interactions between a phage-derived protein and functionalized gold nanorods, we synthesized novel phage mimetic nanorods. The resulting nanovectors showed excellent multi functional properties including target specificity, imaging and photo destruction ability in a model SKBR-3 breast cancer cells. In addition, to gain insight into the molecular interactions involved during internalization of PMNs by SKBR-3 cells, we performed gene expression profiling of cells exposed to PMNs as compared with naive cells. We identified 70 upregulated and 26 downregulated genes responding to PMNs. Heparin binding internalization was identified as most plausible mechanisms of PMNs entry. Members of Major Histocompatibility complex I (MHC class I) were activated by PMNs, leading to enhanced lysosome and proteasome activity. Seven members of poorly annotated G antigen family (GAGE) of genes were upregulated, and may represent novel mechanism of PMNs entry recognition by cells. In summary, we present a versatile technique of PMNs production as any protein isolated from phage libraries selected against any in vitro and in vivo cells can be used as a source to synthesize PMN’s. This study also opens new avenues to understand the role of nanomaterials at the molecular level. Investigate the effect of phage mimetic nanorods onto SKBT-3 cells Two groups were compared, three biological replicates each. One group was control cells and the other was test.

Dataset Information

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles.

Publications

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles.

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