NanoART, NeuroAIDS and CNS Drug Delivery

Ari Nowacek; Howard E Gendelman

Disclosures

Nanomedicine. 2009;4(5):557-574. 

In This Article

Nanomedicine & HIV Disease

Nanomedicines are being developed for HIV therapies. Nanotechnology and the properties of nanomaterials allow for unique ways to inhibit viral mechanisms such as infection, growth and spread. Metal NPs, such as gold and silver, have been extensively researched for their use in imaging, bioassays and therapy,[59,60,61] and are now being studied for their possible use in HIV therapy. Gold has proven to be a good material for nanomedical approaches since it is biocompatible, its NPs can easily be constructed and molecules are readily conjugated to its surface. Gold NPs were conjugated to SDC-1721, a fragment of the potent HIV inhibitor TAK-779, which acts by allosteric inhibition of the CCR5 receptor. Free SDC-1721 has no inhibitory effect on HIV infection; however, SDC-1721-gold NPs displayed activity comparable to that of TAK-779. This suggests that presentation of small molecules on the surface of gold NPs can convert inactive drugs into potent viral inhibitors.[62] The interaction of metal NPs with proteins such as amyloid-ß in Alzheimer's disease and α-synuclein in Parkinson's disease were investigated. However, within this field, an area that has been largely unexplored is the interaction of metal NPs with viruses. Silver NPs can interact with HIV and inhibit infection in vitro. The silver NPs interacted with HIV in a size-dependent manner, as only NPs within the 1-10 nm size range attached to the virus. The suggested mechanism of this interaction occurs through preferential binding to HIV-1 gp120 glycoprotein knobs because of the regular spatial relationships of attached NPs, the center-to-center distance between them and the fact that the exposed sulfur-bearing residues of the glycoprotein knobs of HIV-1 gp120 would be attractive sites for interaction. This is an interesting drug-free method of viral inhibition and more work is needed to investigate the interactions between metal NP and virus.[63]

Residual virus is present in the lymphoid tissues of patients on ART.[64,65] Since viruses isolated from these tissues are also susceptible to antiretroviral medications, it was suggested that insufficient drug exposure is a major cause of viral persistence.[66] In order to address this issue, work was carried out with NPs that target lymphoid tissues. Indinavir (IDV)-NPs composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine were designed. At physiologic pH, IDV binds to the lipid. When administered subcutaneously, the NPs provided IDV concentrations up to 2000% higher in the lymph nodes when compared with the plasma of HIV-infected macaques. However, the plasma concentration achieved was only equivalent to the trough concentration of an oral dose.[67] While it is important to deliver drugs to virus-specific tissue regions, ensuring therapeutic drug levels in the plasma is also required. Therefore, it would be necessary to pair a therapy such as this with one that maintains high drug levels in the plasma.

Since many antiretroviral drugs are rapidly metabolized and eliminated from circulation, one issue that has long plagued HIV therapy has been the poor pharmacokinetics and biodistribution of ART. As such, long-acting parenteral formulations of ART could facilitate treatment maintenance during HIV infection. Rilpivirine, a poorly water-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI), NPs have been manufactured by wet milling in an aqueous carrier and coated with either poloxamer 338 or D-α-tocopheryl polyethylene glycol 1000 succinate surfactants. When compared with intramuscular injections, a single subcutaneous administration resulted in the most stable plasma levels, which were constant at 25 ng/ml for 20 days, followed by a slow subsequent decline to 1-3 ng/ml at 3 months. NPs with a diameter of 200 nm achieved higher and less variable plasma concentrations than 400 or 800 nm NPs. This study provides evidence that subcutaneous injections of antiretrovial NPs (nanoART) may serve as a long-acting therapy.[68]

The pharmacokinetics and biodistribution produced with the use of the two particles described earlier are promising. To be able to achieve stable, long-term drug levels in the plasma, or penetration into poor drug penetrating tissue regions would greatly improve ART. However, the major concern with this method is the route of administration. It is not uncommon to have reactions at the injection site in addition to other untoward side effects when concentrated doses of drugs are injected subcutaneously. This has been an issue for drugs formulated for this type of delivery.[69,70] Issues such as this would first have to be addressed before these types of formulation could be used in humans.

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