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Programmable multistage drug delivery to lymph nodes.

ABSTRACT: Therapeutic delivery selectively to lymph nodes has the potential to address a variety of unmet clinical needs. However, owing to the unique structure of the lymphatics and the size-restrictive nature of the lymph node reticular network, delivering cargo to specific cells in the lymph node cortex and paracortex is difficult. Here, we describe a delivery system to overcome lymphatic and intra-lymph node transport barriers by combining nanoparticles that are rapidly conveyed to draining lymph nodes after administration in peripheral tissues with programmable degradable linkers. This platform enables the controlled release of intra-lymph-mobile small-molecular cargo, which can reach vastly more immune cells throughout the lymph node than either the particles or free compounds alone. The release rate can be programmed, allowing access to different lymph node structures and therefore specific lymphocyte subpopulations. We are thus able to alter the subtypes of drugged lymph node cells to improve immunotherapeutic effects.

SUBMITTER: Schudel A

PROVIDER: S-EPMC7305972 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Programmable multistage drug delivery to lymph nodes.

Schudel Alex A Chapman Asheley Poole AP Yau Mei-Kwan MK Higginson Cody James CJ Francis David Mark DM Manspeaker Margaret Patricia MP Avecilla Alexa Regina Chua ARC Rohner Nathan Andrew NA Finn M G MG Thomas Susan Napier SN

Nature nanotechnology 20200610 6

Therapeutic delivery selectively to lymph nodes has the potential to address a variety of unmet clinical needs. However, owing to the unique structure of the lymphatics and the size-restrictive nature of the lymph node reticular network, delivering cargo to specific cells in the lymph node cortex and paracortex is difficult. Here, we describe a delivery system to overcome lymphatic and intra-lymph node transport barriers by combining nanoparticles that are rapidly conveyed to draining lymph node ...[more]

PMID: 32523099

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Project description:IntroductionHIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4+ T cells and cell-associated RT-SHIV viral RNA.MethodsBetween December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4+ T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co-registered images using MATLAB.ResultsThrough MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4+ target cells and vRNA varied widely by ARV (5.1-100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell-associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value.ConclusionsOur investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.

Dataset Information

Programmable multistage drug delivery to lymph nodes.

Publications

Programmable multistage drug delivery to lymph nodes.

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