Semi-solid prodrug nanoparticles for long-acting delivery of water-soluble antiretroviral drugs within combination HIV therapies

Hobson, James J.; Al-khouja, Amer; Curley, Paul; Meyers, David J.; Flexner, Charles; Siccardi, Marco; Owen, Andrew; Meyers, Caren L. Freel; Rannard, Steve

doi:10.1038/s41467-019-09354-z

Cited by 37 publications

(38 citation statements)

References 25 publications

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“…Our group has used similar strategies to develop hydrophobic prodrug nanoformulations of the HIV integrase inhibitors CAB and dolutegravir that extended their antiretroviral efficacy for more than a month 11,25. Others reported improvements in antiretroviral activity and cellular uptake with other FTC prodrugs 35,45. However, in contrast to our current study, some prodrugs were less hydrophobic and not encased in nanoformulations 46.…”

Section: Discussioncontrasting

confidence: 59%

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<p>Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation</p>

Ibrahim¹,

Bade²,

Lin³

et al. 2019

IJN

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Purpose A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug’s half-life, antiretroviral activities and biodistribution. Methods A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC’s chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated. Results MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and −20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile. Conclusion NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.

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Section: Discussioncontrasting

confidence: 59%

“…While prior studies had attempted to generate a longer acting FTC prodrug, none were fully characterized or developed as a LA ARV strategy 35. In addition, critical measurement of FTC TP formation was lacking as well as in vivo and drug tissue biodistribution assays 35.…”

Section: Discussionmentioning

confidence: 99%

<p>Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation</p>

Ibrahim¹,

Bade²,

Lin³

et al. 2019

IJN

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“…The main focus of HIV research is to develop strategies that prolong protection and target latent HIV + cells. Recent studies have demonstrated designing a long-acting (LA) ARV delivery system would boost the HIV treatment strategy [10][11][12][13]. The nanoformulated ARV delivery system has been shown to enhance drug-solubility, stability, biodistribution, pharmacokinetics, e ciency, and concurrent drug safety, due to reduced ARV associated side-effects [14][15][16].…”

mentioning

confidence: 99%

Targeted Immuno-Antiretroviral HIV Therapeutic Approach to Provide Dual Protection and Boosts Cellular Immunity: A Proof-of-Concept Study

Mandal

et al. 2020

Preprint

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Background: Human immunodeficiency virus (HIV)-infected active and latent C-C motif chemokine receptor-5 (CCR5) expressing long-lived T-cells are the primary barrier to HIV/AIDS eradication. Broadly neutralizing antibodies and latency-reversing agents are the two most promising strategies emerging to achieve ‘functional cure’ against HIV infection. Antiretrovirals (ARVs) have shown to suppress plasma viral loads to non- detectable levels and other strategies have demonstrated a ‘functional cure’ against HIV infection is achievable. Strategies are effective at inducing direct or immune-mediated cell death of latent HIV+ T-cells but have shown respective limitations. We designed a novel targeted ARVs-loaded nanoformulation that combines a CCR5 monoclonal antibody and antiretroviral drugs (ARV) as a dual protection strategy to promote HIV ‘functional cure’. The modified CCR5 monoclonal antibody (xfR5 mAb) surface-coated dolutegravir (DTG) and tenofovir alafenamide (TAF) loaded nanoformulation (xfR5-D+T NPs)Results: The nanoformulation was uniformly sized <250 nm, with 6.5 times enhanced antigen-binding affinity compared to naïve xfR5 mAb, and provided prolonged DTG and TAF intracellular retention. The multivalent and sustained drug release properties of xfR5-D+T NPs enhance the protective efficiency against HIV by approximately 12, 3, and 5 times compared to naïve xfR5 mAb, D+T NP alone, and xfR5 NPs, respectively. Further, the nanoformulation demonstrated high binding-affinity to CCR5 expressing CD4+ cells, monocytes, and other HIV prone/latent T-cells by 25, 2, and 2 times, respectively. Finally, during short-term pre-exposure prophylaxis, the xfR5-D+T NPs induced a protective immunophenotype, with boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. Treatment with xfR5-D+T NPs to HIV-infected T-cells induced a defensive/activated immunophenotype with boosted naïve, Th, central memory, TM, EM, E, and activated cytotoxic T-cells population.Conclusion: This dual-action targeted nanoformulation could potentially become a multifactorial solution to achieve a “functional cure.”

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“…Licensed LAIs are available for contraception [21], schizophrenia [22,23], opioid addiction [24], androgen ablation [25], and hypogonadism [26]. LAI medicines are also in late stage development for the treatment of HIV [27], with preclinical proof-of-concept emerging across infectious diseases [28,29,30].…”

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confidence: 99%

Long-Acting Injectable Statins—Is It Time for a Paradigm Shift?

et al. 2019

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In recent years, advances in pharmaceutical processing technologies have resulted in development of medicines that provide therapeutic pharmacokinetic exposure for a period ranging from weeks to months following a single parenteral administration. Benefits for adherence, dose and patient satisfaction have been witnessed across a range of indications from contraception to schizophrenia, with a range of long-acting medicines also in development for infectious diseases such as HIV. Existing drugs that have successfully been formulated as long-acting injectable formulations have long pharmacokinetic half-lives, low target plasma exposures, and low aqueous solubility. Of the statins that are clinically used currently, atorvastatin, rosuvastatin, and pitavastatin may have compatibility with this approach. The case for development of long-acting injectable statins is set out within this manuscript for this important class of life-saving drugs. An overview of some of the potential development and implementation challenges is also presented.

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Semi-solid prodrug nanoparticles for long-acting delivery of water-soluble antiretroviral drugs within combination HIV therapies

Cited by 37 publications

References 25 publications

<p>Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation</p>

<p>Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation</p>

Targeted Immuno-Antiretroviral HIV Therapeutic Approach to Provide Dual Protection and Boosts Cellular Immunity: A Proof-of-Concept Study

Long-Acting Injectable Statins—Is It Time for a Paradigm Shift?

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