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GM3 Nanoparticles for Sustained Delivery of Anti-Retrovirals to Lymphatic Tissues

Award Number: R01AI132111
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/08/2017
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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GM3 Nanoparticles for Sustained Delivery of Anti-Retrovirals to Lymphatic Tissues - PROJECT ABSTRACT Despite widespread implementation of antiretroviral therapy (ART) that effectively suppresses virus replication in the periphery, HIV persists in tissue reservoirs and accounts for the rapid plasma viral rebound in HIV- infected individuals who have discontinued ART. It is well appreciated that secondary lymphoid tissues represent a drug-privileged site that account for residual viral persistence in HIV-infected individuals on ART. Hence, effective cure and eradication strategies require development of novel approaches that specifically target lymph node-resident HIV reservoirs. An effective strategy to enhance anti-retroviral (ARV) drug concentrations in secondary lymph nodes is to formulate ARVs in carriers such as nanoparticles that promote transport of compounds via the lymphatics to the draining lymph nodes. Additionally, strategies that prevent rapid clearance and maintain inhibitory concentrations of ARVs in lymph nodes for an extended time are needed to effectively suppress persistent virus expression. Hence in this application, we are proposing to develop GM3-containing membrane encapsulated nanoparticle-based approaches to establish long-term tissue depots of ARVs in lymph nodes to suppress residual viral replication. The design of these nanoparticles is based on our recent findings that demonstrate specific capture of GM3 (α2,3-linked sialic acid containing monosialo-dihexosylganglioside) containing membrane encapsulated gold nanoparticles by CD169 expressing primary human myeloid cells such as macrophages and dendritic cells in vitro and co-localization of GM3-gold NPs with CD169+ cells in lymph nodes of mice. Interestingly, capture of GM3-gold NPs resulted in sequestration and preservation within surface accessible non-lysosomal plasma membrane invaginations in CD169+ myeloid cells. Hence, we will exploit these specific interactions between GM3-containing membrane encapsulated nanoparticles and CD169 to achieve both selective targeting of lymph node resident-myeloid cells and sequestration to specialized non-lysosomal compartments for formation of “drug depots” that achieve sustained inhibitory concentrations of ARVs. Finally, we will determine the ability of these novel ARV- containing nanocarriers to suppress virus replication in lymph nodes in a humanized mouse model of HIV-1 infection. We believe these studies are critical to development of virus-eradication strategies for eliminating persistent HIV reservoir.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	7/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $624,640 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	10/15/2021	NON-COMPETING CONTINUATION	$624,640
														Subtotal = $624,640

Issue Date FY: 2021 ( Subtotal = $625,956 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	10/27/2020	NON-COMPETING CONTINUATION	$625,956
														Subtotal = $625,956

Issue Date FY: 2020 ( Subtotal = $637,477 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	11/14/2019	NON-COMPETING CONTINUATION	$637,477
														Subtotal = $637,477

Issue Date FY: 2019 ( Subtotal = $401,724 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	11/1/2018	NON-COMPETING CONTINUATION	$401,724
														Subtotal = $401,724

Issue Date FY: 2018 ( Subtotal = $399,386 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	11/8/2017	NEW	$399,386
														Subtotal = $399,386

Grand Total All Awards = $2,689,183

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GM3 Nanoparticles for Sustained Delivery of Anti-Retrovirals to Lymphatic Tissues

Award Number: R01AI132111

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/08/2017

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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