Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy

Gao, Yu; Kraft, John C.; Yu, Danni; Ho, Rodney J. Y.

doi:10.1016/j.ejpb.2018.04.014

Cited by 42 publications

(35 citation statements)

References 181 publications

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“…However, the physicochemical and biologic properties of the nanotherapeutics can be modulated by the addition of either polyanionic, hydrophobic or hydrophilic side chains on the scaffold. Moreover, the compound can be further modified by the addition of targeting ligands [49]. Indeed, the construction design of the lipid or polymer scaffold is virtually unlimited, but some practical considerations must be taken into account.…”

Section: What Are Nanotherapeutics For Hiv Treatment and Cure?mentioning

confidence: 99%

“…Indeed, the construction design of the lipid or polymer scaffold is virtually unlimited, but some practical considerations must be taken into account. For example, in many current spherical non-covalent nanoparticles of physiological relevant sizes, the pharmaceutical active drugs comprise only 1% of the total molecular weight [49].…”

Section: What Are Nanotherapeutics For Hiv Treatment and Cure?mentioning

confidence: 99%

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The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

Andersen

Tolstrup

2020

Viruses

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Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily pill intake, the treatment is unable to clear the infection from the body. Furthermore, as cART drugs exhibit a much lower concentration in key HIV residual tissues, such as the brain and lymph nodes, there is a rationale for the development of drugs with enhanced tissue penetration. In addition, the treatment, with combinations of multiple different antiviral drugs that display different pharmacokinetic profiles, requires a strict dosing regimen to avoid the emergence of drug-resistant viral strains. An intriguing opportunity lies within the development of long-acting, synthetic scaffolds for delivering cART. These scaffolds can be designed with the goal to reduce the frequency of dosing and furthermore, hold the possibility of potential targeting to key HIV residual sites. Moreover, the synthesis of combinations of therapy as one molecule could unify the pharmacokinetic profiles of different antiviral drugs, thereby eliminating the consequences of sub-therapeutic concentrations. This review discusses the recent progress in the development of long-acting and tissue-targeted therapies against HIV for the delivery of direct antivirals, and examines how such developments fit in the context of exploring HIV cure strategies.

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Section: What Are Nanotherapeutics For Hiv Treatment and Cure?mentioning

confidence: 99%

Section: What Are Nanotherapeutics For Hiv Treatment and Cure?mentioning

confidence: 99%

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

Andersen

Tolstrup

2020

Viruses

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“…Even though the sustained ART-free remission is a well-accepted and effective strategy to control HIV infection, 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 prevention and treatment strategy (6–9). The LA ARV delivery system has shown to enhance drug-solubility, stability, biodistribution, pharmacokinetics, efficiency, and concurrent drug safety, due to reduced ARV associated side-effects, such as mitochondrial toxicity, renal abnormality, and reduced bone mineral density (10–12).…”

Section: Introductionmentioning

confidence: 99%

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

Mandal¹,

Prathipati²,

Belshan³

et al. 2020

Preprint

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Human immunodeficiency virus (HIV)-infected active and latent 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 above strategies have demonstrated a ‘functional cure’ against HIV infection is achievable. Both the above strategies are effective at inducing direct or immune-mediated cell death of latent HIV+ T-cells but have shown respective limitations. In this study, we designed a novel targeted ARVs-loaded nanoformulation that combines the 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) were 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 (t1/2). The multivalent and sustained drug release properties of xfR5-D+T NPs enhance the protection 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. Further, the xfR5-D+T NPs during short-term pre-exposure prophylaxis induced a protective immunophenotype, i.e., boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. Moreover, treatment with xfR5-D+T NPs to HIV-infected T-cells induced a defensive/activated immunophenotype i.e., boosted naïve, Th, boosted central memory, TM, EM, E, and activated cytotoxic T-cells population. Therefore, this dual-action targeted mAb-ARV loaded nanoformulation could potentially become a multifactorial/multilayered solution to achieve a “functional cure.”

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“…Its purpose is to increase the duration of the release, achieve a different mechanism, or delay the initial release [6]. Polymeric nanoparticles have been cited as one kind of nanomedicine that can be advantageous for the treatment of HIV [7,8].…”

Section: Introductionmentioning

confidence: 99%

Development of Innovative Polymer-Based Matricial Nanostructures for Ritonavir Oral Administration

Giaretta

Bianchin

Κanis

et al. 2019

Journal of Nanomaterials

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Ritonavir is used in the treatment of pediatric human immunodeficiency virus infection. The aim of this study was to develop and evaluate innovative polymer-based matricial nanostructures containing ritonavir for a sustained delivery. Two formulations were prepared by interfacial deposition of preformed polymers using Eudragit® RS100 in combination with Polycaprolactone triol 300 (NPR-300) or Polycaprolactone triol 900 (NPR-900). Ritonavir (1 mg mL-1) was incorporated in the formulations. NPR-300 showed a mean size of 559 nm, SPAN of 1.66, zeta potential of 5.9 mV, pH of 4.23, drug content of 73%, and stability under storage for 15 days. NPR-900 showed a mean size of 120 nm, SPAN of 0.83, zeta potential of 7.0 mV, pH of 4.2, drug content of 81%, and stability under storage for 60 days. The ritonavir content was 100% incorporated in both formulations. TEM images demonstrated spherical matricial structures. The ritonavir release in the simulated gastric medium was controlled by incorporation into the nanoparticles, especially into NPR-900. The formulations showed mucoadhesive properties, and the taste evaluation by an in vivo sensory panel indicated that particle size might influence taste perception since the formulation with the larger size of the nanoparticles (NPR-300) worsened the taste of the suspension. The NPR-900 was the most promising nanoparticle formulation for oral delivery of ritonavir.

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Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy

Cited by 42 publications

References 181 publications

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

Development of Innovative Polymer-Based Matricial Nanostructures for Ritonavir Oral Administration

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