Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

Balkundi, Shantanu; Nowacek, Ari S.; Veerubhotla, Ram S.; Chen, Han; Martinez-Skinner, Andrea; Roy, Upal; Mosley, R. Lee; Kanmogne, Georgette D.; Liu, Xinming; Kabanov, Alexander V.; Bronich, Tatiana K.; McMillan, Jo Ellyn; Gendelman, Howard E.

doi:10.2147/ijn.s27830

Cited by 31 publications

(39 citation statements)

References 39 publications

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“…Active research resides in the discovery of new hydrophobic drugs with longer half-lives and protein-binding capacities over what is more commonly prescribed [32, 33]. A key component of this research effort centers upon taking the drug formulations one step further than by simply improving drug half-life or maintaining therapeutic plasma drug concentrations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations

et al. 2015

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Long-acting nanoformulated antiretroviral therapy (nanoART) that target monocyte-macrophage could improve the drug’s half-life and protein binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor-targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly affected several therapeutic factors: drug bioavailability increased as much as 5 times and PD activity improved as much as 100 times. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and infected with HIV-1ADA at a tissue culture infective dose50 of 104 infectious viral particles/ml led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitate drug carriage and facilitate antiretroviral responses.

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations

et al. 2015

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“…ATV-sulfate was procured from Gyma Laboratories of America Inc., Westbury, NY. Nanoformulations using the excipient poloxamer-188 (P188; Sigma-Aldrich, St. Louis, MO) and free base drug were prepared by high-pressure homogenization as described[8, 9]. Drug content was determined by reverse phase high performance liquid chromatography (RP-HPLC)[10] and by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) using a Waters ACQUITY UPLC (Waters, Milford, MA) coupled to an applied Biosystems 4000 Q TRAP quadruple linear ion trap hybrid mass spectrometer (Applied Biosystems/MDS Sciex, Foster City, CA)[16].…”

Section: Methodsmentioning

confidence: 99%

“…Both are safe, well tolerated and efficacious in suppressing viral replication. Therefore, we prepared ATV and RTV ART nanoformulations (nanoART) using a Food and Drug Administration-approved excipient (poloxamer 188; P188) by homogenization procedures developed in our laboratories[8]. Drug encapsulation through such methods results in high ART load per volume ratios with optimal shape and sizes enabling rapid uptake and sustained drug release[3, 5, 9, 10].…”

Section: Introductionmentioning

confidence: 99%

Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice

Dash

Gendelman

Roy

et al. 2012

Aids

120

124

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Objectives Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug compliance and access to viral reservoirs. Design Atazanvir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgcnull (NSG) mice. Methods NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and nanotoxicology. CD34+ human hematopoietic stem cells were transplantation at birth in NSG mice. The mice were infected with HIV-1ADA at 5 months of age and 8 weeks later, infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4+ T cell count, lymphoid tissue and brain pathology were evaluated. Results NanoART treatments by 6 once a week injections reduced viral loads >1000 fold and protected CD4+ T cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. Conclusions Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.

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“…Nanosuspensions are aqueous suspensions containing poorly water-soluble drug crystals and stabilizers [15, 20, 28]. One or several excipients and appropriate buffers are used to prevent crystal growth or particle aggregation.…”

Section: Sustained-release Arv Formulationsmentioning

confidence: 99%

Long-acting slow effective release antiretroviral therapy

Edagwa

McMillan

Sillman

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Advances in the development of long acting antiretroviral therapy (ART) can revolutionize current treatments for HIV/AIDS. We have coined the term long active slow effective release ART (LASER ART) based on properties of slow drug dissolution, poor water-solubility, excellent bioavailability, limited off target systemic toxicities, and excellent patient treatment adherence. Drug carrier technologies characterized by high payload of antiretroviral drugs (ARVs) in a single carrier are being developed to improve the pharmacokinetics and pharmacodynamics of the nanoformulated ART (nanoART). Additionally, surface modification of slow release antiretroviral carriers with targeting ligands has facilitated receptor-mediated transport across physiological barriers serves to improve therapeutic outcomes. Areas covered This review highlights current developments of reservoir targeted LASER ART delivery platforms that have the potential to improve HIV/AIDS therapeutic outcomes. Such nanoART delivery platforms include decorated multifunctional nano- and micro- particles, prodrugs and polymer conjugates. Therapeutic strategies such as anti-inflammatory and neuroprotective agents and CRISPR/Cas 9 based gene-editing technologies that affect drug depots, boost ART effectiveness and facilitate viral clearance are discussed. Expert opinion The persistence of HIV-1 in its lymphoid, gut and nervous system reservoirs poses a major challenge to viral eradication. Emerging innovative strategies for effective medicines and slow release products to target intracellular pathogens, immune based interventions, genome-editing technologies, compounds that sustain drug depots and combinations of nanoART and image contrast agents have the potential to meet the unmet clinical needs of HIV patients. Such efforts will bring the medicines to sites of active viral replication and accelerate viral clearance.

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Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

Cited by 31 publications

References 39 publications

Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations

Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations

Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice

Long-acting slow effective release antiretroviral therapy

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