Int J Nanomedicine. 2015 Feb 4;10:1077-93. doi: 10.2147/IJN.S76517.

Sustained-release nanoART formulation for the treatment of neuroAIDS.

Jayant RD, Atluri VS, Agudelo M, Sagar V, Kaushik A, Nair M.

Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.

 

Abstract

A novel approach was developed for the coencapsulation of an anti-HIV drug (tenofovir) and a latency-breaking agent (vorinostat), using magnetically guided layer-by-layer (LbL) assembled nanocarriers for the treatment of neuroAIDS. Ultrasmall iron oxide (Fe3O4) nanoparticles (10±3 nm) were synthesized and characterized. The LbL technique was used to achieve a sustained release profile, and application of 2 bilayers ([tenofovir+dextran sulphate]2+vorinostat) to magnetic nanoparticles resulted in a 2.8 times increase in drug (tenofovir) loading and also resulted in an increase in the drug release period by 30-fold, with 100% drug release in sustained manner over a period of 5 days with the simultaneous stimulation of latent HIV expression. Nanoformulation showed a good blood-brain barrier transmigration ability (37.95%±1.5%) with good in vitro antiviral efficacy (~33% reduction of p24 level) over a period of 5 days after HIV infection in primary human astrocytes, with good cell viability (>90%). Hence, LbL arrangements of drugs on magnetic nanoparticles provides sustained release and, therefore, may improve the patient’s adherence to therapy and lead to better compliance.

KEYWORDS: anti-HIV drug; blood–brain barriers; latency; layer-by-layer; magnetic nanocarriers; neuroAIDS; sustained release

PMID: 25709433

 

Supplement

Nonadherence to antiretroviral therapy among AIDS patients significantly undermines the effort to prevent HIV disease progression. Patients, in large, requires lifelong adherence to be effective. Most antiretroviral drugs have short half-lives and, in turn, need to be in body all time in order to check the virus replication. It is believed that missing medication dose-even once-can provide opportunity for viruses to replicate such that medication resistance HIV strain may develop. Nevertheless, many reasons could prevent patients from taking proper medications; such as recreational drug use, complexity of dosing, low health literacy, chaotic lifestyle, side effects, or psychological emotions2. Therefore, a better management of AIDS Patients could be greatly achieved by reducing their adherence to medications, preferably by providing better-sustained drug formulations. In addition, efforts should be made towards targeting hidden latent virus in the body sanctuaries such as brain, which naturally function as continuous virus production center to periphery. In spite of significant advances in Highly Active Anti-Retroviral Therapy (HAART), the elimination of HIV-1 reservoirs from the central nervous system (CNS) remains a formidable task. This is mainly attributed to the inability of antiretroviral therapy (ART) to penetrate blood brain barrier (BBB) after systemic administration. Many antiretroviral (ARV) drugs remain deprived in the brain3. Recent studies have shown that Vorinostat, among other agents, is being used as HIV reactivating or latency breaking agent to break the latency 4, 5. Therefore, a sustained release formulation of latency-breaking agent along with anti-retroviral drugs could serve multifunctional purpose. Where in one hand sustained drug release may cause reduced adherence, in other hand, combination of latency breaking and anti-HIV agent could eradicate virus reservoir. Practice of nanotechnology in medicine has shown exciting prospect for development of a novel drug delivery system to achieve the desired therapeutic levels of anti-HIV drugs and HIV reactivating agent across the BBB6-9. Nevertheless, all existing nano-based drug delivery methods have one or more major limitations that affect the target specificity, drug delivery, drug release and bioavailability of desired amount of drugs at the targeted site. So, from a drug delivery point of view, a fast and effective way of delivering drugs in the brain and maintaining its sustained release is very much needed to eradicate the latent HIV in the brain and to reduce the therapeutic adherence. So to achieve this goal, we have develop a novel Layer-by-Layer (LbL)10, 11 nanoassembly of anti-HIV drug and latency breaking agent on magnetic nanoparticles (MNP) that can be utilized to attain the sustain release profile of drug for desired period of time (Fig.2).

RDJ fig1

Fig. 1 HAART Non- Adherence1 Statistics

 

RDJ fig2

Fig 2: Schematic representation of LbL assembly of drugs on MNP

 

The movement of MNP can be “remote controlled” for its effective penetration across the BBB by applying an external magnetic force (0.3-0.8 Tesla) 12, 13. Complementarily, LbL arrangements of drug on MNP will provide sustained release and, therefore, may improve patient’s adherence compliance. Accordingly following specific aims are proposed using this novel strategy. In conclusion, this is the first ever attempt to couple LbL assembly on MNP (7-10 nm) to deliver combination of HIV latency breaking agent (Vorinostat) and HIV drug (Tenofovir) across BBB in a non-invasive manner (by magnetic force) to activate latent HIV and thus to eradicate HIV reservoir in the brain concurrently. The developed formulation will anticipated to overcome many of the physiological barriers to activate latent virus in CNS and deliver the drugs across BBB in sustained manner to completely eradicate activated virus and reducing the patient’s adherence to medications. In addition to eliminate the latent HIV reservoir in the brain, as proposed, this invented technology will have universal applicability against variety of other CNS diseases for sustained drug targeting in the brain in a non-invasive manner. This novel technology of specific drug targeting to the brain using MNP-LbL assembly will be useful for reactivation of latent HIV and final eradication of HIV from CNS reservoir and will be a clinically viable approach in reducing patient’s adherence on medications especially in drug abusing HIV-infected subjects.

 

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