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

Abstract

Medication adherence and insufficient drug levels are central to HIV/AIDS disease progression. Recently, Fletcher et al. confirmed that HIV patients on oral antiretroviral therapy had lower intracellular drug concentrations in lymph nodes than in blood. For instance, in the same patient, multiple lymph node drug concentrations were as much as 99 % lower than in blood. This study built upon our previous finding that HIV patients taking oral indinavir had 3-fold lower mononuclear cell drug concentrations in lymph nodes than in blood. As a result, an association between insufficient lymph node drug concentrations in cells and persistent viral replication has now been validated. Lymph node cells, particularly CD4 T lymphocytes, host HIV infection and persistence; CD4 T cell depletion in blood correlates with AIDS progression. With established drug targets to overcome drug insufficiency in lymphoid cells and tissues, we have developed and employed a “Systems Approach” to engineer multi-drug-incorporated particles for HIV treatment. The goal is to improve lymphatic HIV drug exposure to eliminate HIV drug insufficiency and disease progression. We found that nano-particulate drugs that absorb, transit, and retain in the lymphatic system after subcutaneous dosing improve intracellular lymphatic drug exposure and overcome HIV lymphatic drug insufficiency. The composition, physical properties, and stability of the drug nanoparticles contribute to the prolonged and enhanced drug exposure in lymphoid cells and tissues. In addition to overcoming lymphatic drug insufficiency and potentially reversing HIV infection, targeted drug nanoparticle properties may extend drug concentrations and enable the development of long-acting HIV drug therapy for enhanced patient compliance.

Harnessing nanostructured systems for improved treatment and prevention of HIV disease

“…Although magnetic targeting of magnetic liposomes to the viral reserve tissues is possible, it is not necessary to improve accumulation of ARVs at the sites of action, and it complicates the production of the liposomes and the execution of the therapy . The Ho lab was able to demonstrate improved lymph node accumulation of PEGylated liposomes encapsulating three ARV drugs .…”

“…Although magnetic targeting of magnetic liposomes to the viral reserve tissues is possible, it is not necessary to improve accumulation of ARVs at the sites of action, and it complicates the production of the liposomes and the execution of the therapy . The Ho lab was able to demonstrate improved lymph node accumulation of PEGylated liposomes encapsulating three ARV drugs . Hydrophilic tenofovir (TFV) was trapped inside the aqueous core and attached to the hydrophilic heads of the phospholipids, and hydrophobic ritonavir (RTV) and lopinavir (LPV) were stored within the hydrophobic core of the phospholipid bilayer .…”

“…The Ho lab was able to demonstrate improved lymph node accumulation of PEGylated liposomes encapsulating three ARV drugs . Hydrophilic tenofovir (TFV) was trapped inside the aqueous core and attached to the hydrophilic heads of the phospholipids, and hydrophobic ritonavir (RTV) and lopinavir (LPV) were stored within the hydrophobic core of the phospholipid bilayer . 24 hr after subcutaneous delivery of the three free ARVs in a primate animal model, virtually no detectable concentration of RTV or LPV was found in LNMCs and 224.2–287.2 ng/mL of TFV was found in LNMCs .…”

“…Hydrophilic tenofovir (TFV) was trapped inside the aqueous core and attached to the hydrophilic heads of the phospholipids, and hydrophobic ritonavir (RTV) and lopinavir (LPV) were stored within the hydrophobic core of the phospholipid bilayer . 24 hr after subcutaneous delivery of the three free ARVs in a primate animal model, virtually no detectable concentration of RTV or LPV was found in LNMCs and 224.2–287.2 ng/mL of TFV was found in LNMCs . Subcutaneous injection of liposomes encapsulating the ARVs resulted in accumulation of more than 1,200 ng/mL of LPV and 1,600 ng/mL of RTV in the LNMCs .…”

“…24 hr after subcutaneous delivery of the three free ARVs in a primate animal model, virtually no detectable concentration of RTV or LPV was found in LNMCs and 224.2–287.2 ng/mL of TFV was found in LNMCs . Subcutaneous injection of liposomes encapsulating the ARVs resulted in accumulation of more than 1,200 ng/mL of LPV and 1,600 ng/mL of RTV in the LNMCs . Liposomal encapsulation did not improve the LNMC concentration of TFV, but it did improve the plasma concentration of the ARV .…”