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T cells enhance gold nanoparticle delivery to tumors in vivo.

Kennedy LC, Bear AS, Young JK, Lewinski NA, Kim J, Foster AE, Drezek RA - Nanoscale Res Lett (2011)

Bottom Line: We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production).In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution.Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA. aefoster@txccc.org.

ABSTRACT
Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

No MeSH data available.


Related in: MedlinePlus

AuNP-loaded T cells migrate to tumors in vivo. (A) T cells were retrovirally modified to express firefly luciferase then loaded in the presence of 0.5 nM AuNP for 24 h. Cells were subsequently injected intravenously into SCID mice bearing subcutaneous xenografted LCL tumors. Bioluminescent imaging of AuNP-T cell biodistribution at 48 h post-injection showing AuNP-T cell localization at the tumor site (red circle) and within the spleen. (B) Resected tumors were analyzed by bright field imaging (top row) and immunohistochemistry for human CD3 expression and dark field imaging (bottom row) to indicate the presence of AuNPs. Red arrows indicate the colocalization of CD3+ T cells and AuNPs within the tumor.
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Figure 3: AuNP-loaded T cells migrate to tumors in vivo. (A) T cells were retrovirally modified to express firefly luciferase then loaded in the presence of 0.5 nM AuNP for 24 h. Cells were subsequently injected intravenously into SCID mice bearing subcutaneous xenografted LCL tumors. Bioluminescent imaging of AuNP-T cell biodistribution at 48 h post-injection showing AuNP-T cell localization at the tumor site (red circle) and within the spleen. (B) Resected tumors were analyzed by bright field imaging (top row) and immunohistochemistry for human CD3 expression and dark field imaging (bottom row) to indicate the presence of AuNPs. Red arrows indicate the colocalization of CD3+ T cells and AuNPs within the tumor.

Mentions: In vivo AuNP-T cell migration to tumor sites was first examined using bioluminescent imaging and histology. T cells were first genetically modified to express firefly luciferase and then subsequently loaded with AuNPs. Bioluminescent imaging 48 h post-intravenous injection of AuNP-T cells demonstrate specific migration of the T cells to subcutaneous LCL tumors in immune deficient SCID mice (Figure 3a). This timepoint was selected based on previous studies that have demonstrated T cell localization to tumor sites 48 h post-infusion [32,33]. We next resected the tumors and performed histology to determine if AuNPs and T cells co-localized within the tumor. Immunohistochemical staining using CD3 antibody (a pan-T cell marker) demonstrated infiltration of T cells into the tumor (Figure 3b). In addition, areas of increased scatter in the darkfield images correlated well with areas of CD3+ staining. This observation demonstrates that the T cells maintain internalized AuNPs during in vivo migration to the tumor site.


T cells enhance gold nanoparticle delivery to tumors in vivo.

Kennedy LC, Bear AS, Young JK, Lewinski NA, Kim J, Foster AE, Drezek RA - Nanoscale Res Lett (2011)

AuNP-loaded T cells migrate to tumors in vivo. (A) T cells were retrovirally modified to express firefly luciferase then loaded in the presence of 0.5 nM AuNP for 24 h. Cells were subsequently injected intravenously into SCID mice bearing subcutaneous xenografted LCL tumors. Bioluminescent imaging of AuNP-T cell biodistribution at 48 h post-injection showing AuNP-T cell localization at the tumor site (red circle) and within the spleen. (B) Resected tumors were analyzed by bright field imaging (top row) and immunohistochemistry for human CD3 expression and dark field imaging (bottom row) to indicate the presence of AuNPs. Red arrows indicate the colocalization of CD3+ T cells and AuNPs within the tumor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3211348&req=5

Figure 3: AuNP-loaded T cells migrate to tumors in vivo. (A) T cells were retrovirally modified to express firefly luciferase then loaded in the presence of 0.5 nM AuNP for 24 h. Cells were subsequently injected intravenously into SCID mice bearing subcutaneous xenografted LCL tumors. Bioluminescent imaging of AuNP-T cell biodistribution at 48 h post-injection showing AuNP-T cell localization at the tumor site (red circle) and within the spleen. (B) Resected tumors were analyzed by bright field imaging (top row) and immunohistochemistry for human CD3 expression and dark field imaging (bottom row) to indicate the presence of AuNPs. Red arrows indicate the colocalization of CD3+ T cells and AuNPs within the tumor.
Mentions: In vivo AuNP-T cell migration to tumor sites was first examined using bioluminescent imaging and histology. T cells were first genetically modified to express firefly luciferase and then subsequently loaded with AuNPs. Bioluminescent imaging 48 h post-intravenous injection of AuNP-T cells demonstrate specific migration of the T cells to subcutaneous LCL tumors in immune deficient SCID mice (Figure 3a). This timepoint was selected based on previous studies that have demonstrated T cell localization to tumor sites 48 h post-infusion [32,33]. We next resected the tumors and performed histology to determine if AuNPs and T cells co-localized within the tumor. Immunohistochemical staining using CD3 antibody (a pan-T cell marker) demonstrated infiltration of T cells into the tumor (Figure 3b). In addition, areas of increased scatter in the darkfield images correlated well with areas of CD3+ staining. This observation demonstrates that the T cells maintain internalized AuNPs during in vivo migration to the tumor site.

Bottom Line: We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production).In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution.Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA. aefoster@txccc.org.

ABSTRACT
Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

No MeSH data available.


Related in: MedlinePlus