Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Kraft, John C.; McConnachie, Lisa A.; Koehn, Josefin; Kinman, Loren; Collins, Carol; Shen, Danny D.; Collier, Ann C.; Ho, Rodney J. Y.

doi:10.1097/qad.0000000000001405

Cited by 47 publications

(77 citation statements)

References 15 publications

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“…This is relevant for lipid-based nanotherapeutic ARV delivery, based on subcutaneous administration. For example, lymphatic tissue localization of lipid-indinavir (IDV) particles via a passive diffusion strategy were explored [110][111][112][113][114].…”

Section: Increasing Access Of Drugs To Lymphoid Tissuesmentioning

confidence: 99%

“…The mechanism causing the biodistribution of nanoparticles in the lymphatic system have been investigated [115]. Specifically, it was shown that nanoparticles administered subcutaneously were retained intra-lymphatically and subsequently distributed to the entire mouse body [114,115]. This effect was ascribed to the relatively large size of the molecules (60-120 nm) preventing extravasation from lymph vessels, which blocks release into the blood stream and enables transport from lymph node to lymph node through interconnected lymphatic vessels [115] (such effect shown in Figure 2).…”

Section: Increasing Access Of Drugs To Lymphoid Tissuesmentioning

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: Increasing Access Of Drugs To Lymphoid Tissuesmentioning

confidence: 99%

Section: Increasing Access Of Drugs To Lymphoid Tissuesmentioning

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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“…However, as with the long-acting agents described above, this was a single agent formulation and presented resistance risks. We have since published studies on a similar nano-drug particle formulation containing three antiretroviral agents, with proven clinical efficacy and safety profiles, that are directed at two viral targets (protease and reverse transcriptase of HIV) in the presence of lipid excipients (DSPC and DSPE-mPEG 2000 ) [53,57]. In both reports, drug-lipid NP formulations were delivered via subcutaneous injection and relatively high concentrations of all three drugs in the HIV host cells of lymph nodes and blood were observed.…”

Section: Progression Of Drug Combination Nps To Primate and Human Tesmentioning

confidence: 99%

“…The ability to co-formulate drugs with disparate physical chemical characteristics and subsequently deliver them in a targeted manner in a fixed-dose combination represents significant progress in drug design and nanomedicine. With validated processes in place, and verified long-acting plasma and cellular pharmacokinetics, this anti-HIV drug combination nanoformulation is now referred to as TLC-ART 101 and is a candidate for further clinical development [57]. …”

Section: Progression Of Drug Combination Nps To Primate and Human Tesmentioning

confidence: 99%

“…This work will need to go beyond mere dose and drug selection, and will require incorporating DcNP formulation and cell targeting knowledge and understanding. This will require efficient and versatile DcNP delivery platforms that can stably combine multiple hydrophilic and hydrophobic APIs at different molar ratios, such as the platform we have developed [53,57]. Furthermore, a rapid, robust, reproducible and scalable manufacturing process, such as the microfluidic systems being marketed by Precision NanoSystems Inc., for commercial large batch production of drug-loaded nanoparticles, would be beneficial [71].…”

Section: Future Outlook – Personalised Drug Combination Particles In mentioning

confidence: 99%

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Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

McConnachie

et al. 2018

Journal of Drug Targeting

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The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine.

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Recent advances in combination of microneedles and nanomedicines for lymphatic targeted drug delivery

Permana

Nainu

Moffatt

et al. 2021

WIREs Nanomed Nanobiotechnol

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Numerous diseases have been reported to affect the lymphatic system. As such, several strategies have been developed to deliver chemotherapeutics to this specific network of tissues and associated organs. Nanotechnology has been exploited as one of the main approaches to improve the lymphatic uptake of drugs. Different nanoparticle approaches utilized for both active and passive targeting of the lymphatic system are discussed here. Specifically, due to the rich abundance of lymphatic capillaries in the dermis, particular attention is given to this route of administration, as intradermal administration could potentially result in higher lymphatic uptake compared to other routes of administration. Recently, progress in microneedle research has attracted particular attention as an alternative for the use of conventional hypodermic injections. The benefits of microneedles, when compared to intradermal injection, are subsequently highlighted. Importantly, microneedles exhibit particular benefit in relation to therapeutic targeting of the lymphatic system, especially when combined with nanoparticles, which are further discussed. However, despite the apparent benefits provided by this combination approach, further comprehensive preclinical and clinical studies are now necessary to realize the potential extent of this dual‐delivery platform, further taking into consideration eventual usability and acceptability in the intended patient end‐users. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Cited by 47 publications

References 15 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

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

Recent advances in combination of microneedles and nanomedicines for lymphatic targeted drug delivery

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