Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy

Hyunjoon Kim; Drishti Sehgal; Tamara A. Kucaba; David M Ferguson; Thomas S Griffith; Jayanth Panyam

doi:10.1039/c8nr07201a

Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy

Hyunjoon Kim, Drishti Sehgal, Tamara A. Kucaba, David M Ferguson, Thomas S Griffith, Jayanth Panyam

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Abstract

Synthetic imidazoquinoline-based toll-like receptor (TLR) 7/8 bi-specific agonists are promising vaccine adjuvants that can induce maturation of dendritic cells (DCs) and activate them to secrete pro-inflammatory cytokines. However, in vivo efficacy of these small molecule agonists is often hampered by their fast clearance from the injection site, limiting their use to topical treatments. In this study, we investigated the use of acidic pH-responsive poly(lactide-co-glycolide) (PLGA) nanoparticles for endo-lysosome specific release of 522, a novel TLR7/8 agonist. Bicarbonate salt was incorporated into the new formulation to generate carbon dioxide (CO₂) gas at acidic pH, which can disrupt the polymer shell to rapidly release the payload. Compared to conventional PLGA nanoparticles, the pH responsive formulation resulted in 33-fold higher loading of 522. The new formulation demonstrated acid-responsive CO₂ gas generation and drug release. The acid-responsive formulation increased the in vitro expression of co-stimulatory molecules on DCs and improved antigen-presentation via MHC I, both of which are essential for CD8 T cell priming. In vivo studies showed that the pH-responsive formulation elicited stronger antigen-specific CD8 T cell and natural killer (NK) cell responses than conventional PLGA nanoparticles, resulting in enhanced anticancer efficacy in a murine melanoma tumor model. Our results suggest that acidic-pH responsive, gas-generating nanoparticles are an efficient TLR7/8 agonist delivery platform for cancer immunotherapy.

Original language	English (US)
Pages (from-to)	20851-20862
Number of pages	12
Journal	Nanoscale
Volume	10
Issue number	44
DOIs	https://doi.org/10.1039/c8nr07201a
State	Published - Nov 28 2018

Bibliographical note

Funding Information:
We thank Guillermo Marques in the University Imaging Center (University of Minnesota) for ultrasound imaging training and Elizabeth Lundstrom in the Geochemical lab (University of Minnesota) for ICP-EOS analysis. We also thank Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from the NSF through the MRSEC program (The Hitachi SU8320 cryoSEM and cryospecimen preparation system were provided by NSF MRI DMR-1229263), for the Cryo-TEM imaging.

Funding Information:
This work was supported by the Grant in aid program, University of Minnesota (to J. P.), the GAP award (to J. P.), the Masonic Cancer Center, University of Minnesota (to T. S. G.), the Prostate and Urological Cancer Translational Working Group (to T. S. G.), and the Randy Shaver Cancer Research & Community Fund (to T. S. G., D. M. F.).

Publisher Copyright:
© 2018 The Royal Society of Chemistry.

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title = "Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy",

abstract = "Synthetic imidazoquinoline-based toll-like receptor (TLR) 7/8 bi-specific agonists are promising vaccine adjuvants that can induce maturation of dendritic cells (DCs) and activate them to secrete pro-inflammatory cytokines. However, in vivo efficacy of these small molecule agonists is often hampered by their fast clearance from the injection site, limiting their use to topical treatments. In this study, we investigated the use of acidic pH-responsive poly(lactide-co-glycolide) (PLGA) nanoparticles for endo-lysosome specific release of 522, a novel TLR7/8 agonist. Bicarbonate salt was incorporated into the new formulation to generate carbon dioxide (CO2) gas at acidic pH, which can disrupt the polymer shell to rapidly release the payload. Compared to conventional PLGA nanoparticles, the pH responsive formulation resulted in 33-fold higher loading of 522. The new formulation demonstrated acid-responsive CO2 gas generation and drug release. The acid-responsive formulation increased the in vitro expression of co-stimulatory molecules on DCs and improved antigen-presentation via MHC I, both of which are essential for CD8 T cell priming. In vivo studies showed that the pH-responsive formulation elicited stronger antigen-specific CD8 T cell and natural killer (NK) cell responses than conventional PLGA nanoparticles, resulting in enhanced anticancer efficacy in a murine melanoma tumor model. Our results suggest that acidic-pH responsive, gas-generating nanoparticles are an efficient TLR7/8 agonist delivery platform for cancer immunotherapy.",

author = "Hyunjoon Kim and Drishti Sehgal and Kucaba, {Tamara A.} and Ferguson, {David M} and Griffith, {Thomas S} and Jayanth Panyam",

note = "Funding Information: We thank Guillermo Marques in the University Imaging Center (University of Minnesota) for ultrasound imaging training and Elizabeth Lundstrom in the Geochemical lab (University of Minnesota) for ICP-EOS analysis. We also thank Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from the NSF through the MRSEC program (The Hitachi SU8320 cryoSEM and cryospecimen preparation system were provided by NSF MRI DMR-1229263), for the Cryo-TEM imaging. Funding Information: This work was supported by the Grant in aid program, University of Minnesota (to J. P.), the GAP award (to J. P.), the Masonic Cancer Center, University of Minnesota (to T. S. G.), the Prostate and Urological Cancer Translational Working Group (to T. S. G.), and the Randy Shaver Cancer Research & Community Fund (to T. S. G., D. M. F.). Publisher Copyright: {\textcopyright} 2018 The Royal Society of Chemistry.",

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AU - Griffith, Thomas S

AU - Panyam, Jayanth

N1 - Funding Information: We thank Guillermo Marques in the University Imaging Center (University of Minnesota) for ultrasound imaging training and Elizabeth Lundstrom in the Geochemical lab (University of Minnesota) for ICP-EOS analysis. We also thank Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from the NSF through the MRSEC program (The Hitachi SU8320 cryoSEM and cryospecimen preparation system were provided by NSF MRI DMR-1229263), for the Cryo-TEM imaging. Funding Information: This work was supported by the Grant in aid program, University of Minnesota (to J. P.), the GAP award (to J. P.), the Masonic Cancer Center, University of Minnesota (to T. S. G.), the Prostate and Urological Cancer Translational Working Group (to T. S. G.), and the Randy Shaver Cancer Research & Community Fund (to T. S. G., D. M. F.). Publisher Copyright: © 2018 The Royal Society of Chemistry.

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N2 - Synthetic imidazoquinoline-based toll-like receptor (TLR) 7/8 bi-specific agonists are promising vaccine adjuvants that can induce maturation of dendritic cells (DCs) and activate them to secrete pro-inflammatory cytokines. However, in vivo efficacy of these small molecule agonists is often hampered by their fast clearance from the injection site, limiting their use to topical treatments. In this study, we investigated the use of acidic pH-responsive poly(lactide-co-glycolide) (PLGA) nanoparticles for endo-lysosome specific release of 522, a novel TLR7/8 agonist. Bicarbonate salt was incorporated into the new formulation to generate carbon dioxide (CO2) gas at acidic pH, which can disrupt the polymer shell to rapidly release the payload. Compared to conventional PLGA nanoparticles, the pH responsive formulation resulted in 33-fold higher loading of 522. The new formulation demonstrated acid-responsive CO2 gas generation and drug release. The acid-responsive formulation increased the in vitro expression of co-stimulatory molecules on DCs and improved antigen-presentation via MHC I, both of which are essential for CD8 T cell priming. In vivo studies showed that the pH-responsive formulation elicited stronger antigen-specific CD8 T cell and natural killer (NK) cell responses than conventional PLGA nanoparticles, resulting in enhanced anticancer efficacy in a murine melanoma tumor model. Our results suggest that acidic-pH responsive, gas-generating nanoparticles are an efficient TLR7/8 agonist delivery platform for cancer immunotherapy.

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Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy

Abstract

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Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy

Abstract

Bibliographical note

UN SDGs

Publisher link

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University Imaging Centers

Vevo 2100

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