Response to

Abstract

In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.

Systems Approach to targeted and long-acting HIV/AIDS therapy

“…When indinavir particles were given subcutaneously to primates, they resulted in greatly enhanced drug concentrations in lymph nodes throughout the body when compared to free indinavir given via the traditional oral route (Table 2). These particles also distributed to lymph nodes throughout the lymphatic system, from inguinal and mesenteric to submandibular and other visceral and peripheral nodes, a finding that we have validated in subsequent studies [11, 17]. Additionally, HIV-infected primates given the indinavir-lipid particles showed a reduction in viral load in plasma and lower residual virus levels in lymph nodes, as well as reversal of CD4 T cell decline, indicating a disruption in the natural course of disease progression [17].…”

“…To address this question, the lymph nodes of HIV patients on the oral HIV protease inhibitor indinavir were collected and peripheral blood mononuclear cells (which include CD4 T lymphocytes) in blood and mononuclear cells from lymph nodes were isolated [11]. At the time of tissue and cell collection, these patients were on oral indinavir therapy and had reached steady-state drug levels in blood after multiple doses of indinavir.…”

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

“…Although the exact fate of SC-injected lipid-associated IDV NPs is not well characterized, it is likely that lipid–IDV NPs were trapped in LNs throughout the lymphatic system. The Ho group further optimized a lipid NP formulation [114]. Compared to previous formulations, new lipid-IDV NP provided 6-fold higher IDV concentrations in LNs of the macaque/SIV model and enhanced drug exposure in blood.…”

Long-acting three-drug combination anti-HIV nanoparticles enhance drug exposure in primate plasma and cells within lymph nodes and blood

“…Drug nanoparticles have the potential to overcome lymphatic drug insufficiency [9]. We previously developed and demonstrated in primates a lipid nanoparticle (LNP) containing indinavir (IDV) that enhanced drug levels in all analyzed lymph nodes [4,10]. Also, IDV in LNPs enhanced intracellular drug concentrations in peripheral blood mononuclear cells (PBMCs), prolonged plasma residence time, reversed CD4 + T-cell decline, and suppressed viral RNA in both plasma and lymph nodes [10].…”

“…We previously developed and demonstrated in primates a lipid nanoparticle (LNP) containing indinavir (IDV) that enhanced drug levels in all analyzed lymph nodes [4,10]. Also, IDV in LNPs enhanced intracellular drug concentrations in peripheral blood mononuclear cells (PBMCs), prolonged plasma residence time, reversed CD4 + T-cell decline, and suppressed viral RNA in both plasma and lymph nodes [10]. Building on findings with IDV-LNPs, we have developed an anti-HIV LNP containing two protease inhibitors, lopinavir (LPV) and ritonavir (RTV), and a reverse transcriptase inhibitor, tenofovir (TFV), for simultaneous, triple drug delivery to HIV host cells in blood and lymph.…”