Using Glycosaminoglycan/Chemokine Interactions for the Long-Term Delivery of 5P12-RANTES in HIV Prevention

Wang, Nick X.; Sieg, Scott F.; Lederman, Michael M.; Offord, Robin E.; Hartley, Oliver; Recum, Horst A. von

doi:10.1021/mp3007242

Cited by 15 publications

(15 citation statements)

References 38 publications

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“…We observed this in other similar, although chemically different affinity-based drug delivery systems where drug with a 6 hr solution half-life was shown to maintain full activity out to 30 days. 21 The capacity for affinity to prolong the release of doxycycline beyond that of diffusion-only systems is smaller than what we observed for other drugs. 17 This is predicted since the binding affinity for doxycycline is smaller than that reported for those other systems.…”

Section: Discussioncontrasting

confidence: 61%

“…Additionally we hypothesize that drug stability could be improved in the aqueous environment by locking drug mobility while in the affinity‐matrix and thereby reducing reaction and molecular breakdown potential. We observed this in other similar, although chemically different affinity‐based drug delivery systems where drug with a 6 hr solution half‐life was shown to maintain full activity out to 30 days …”

Section: Discussionsupporting

confidence: 58%

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Providing sustained transgene induction through affinity‐based drug delivery

Rivera-Delgado

Ward

Recum

2016

J Biomedical Materials Res

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Small molecule drug activators of gene expression have been used in applications ranging from gene therapy, to tissue engineering and regenerative medicine. One concern is that for sustained gene expression, a long-term, controlled delivery system is needed. Insoluble polymers containing a high proportion of cyclodextrin (CD) affinity groups have been shown to prolong drug delivery far beyond that capable of polymers relying on diffusion alone. In this study we evaluate the capacity of such polymers to deliver the transgene inducer doxycycline. Our results show that initial drug loading is proportional to affinity, with ∼8% loading in high-affinity γ-CD polymers; ∼7% loading in moderate-affinity β-CD polymers; and only ∼4.5% loading in the non-affinity control polymer made from linear dextran. When release aliquots from these polymers were incubated with cells genetically modified for inducible transgene expression we observed activation of transgene expression for up to three weeks from samples released by affinity-based polymers. We showed that drug stability is maintained over the course of the study using a bacterial zone of inhibition assay where again affinity-based polymers show sustained availability of drug, weeks longer than non-affinity controls. Lastly we provide theoretical calculations of strength of binding interactions between cyclodextrins and many additional transgene inducers demonstrating the broad utility of this delivery platform.

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionsupporting

confidence: 58%

Providing sustained transgene induction through affinity‐based drug delivery

Rivera-Delgado

Ward

Recum

2016

J Biomedical Materials Res

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“…In vitro dissolution testing of 5P12-RANTES gels. Simulated vaginal fluid (SVF), modified to include an increased BSA concentration (0.1%, wt/wt) to reduce the adsorption of 5P12-RANTES to the glassware, was prepared according to previously described methods (73,75). The SVF was filtered immediately after preparation (sterile Millex-GS syringe filter unit, mixed cellulose ester membrane; Millipore, UK) and stored for a maximum of 3 days at 4 to 6°C prior to use.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

McBride

Dias

Cameron

et al. 2017

Antimicrob Agents Chemother

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5P12-RANTES, a chemokine analogue that potently blocks the HIV CCR5 coreceptor, is being developed as both a vaginal and rectal microbicide for prevention of sexual transmission of HIV. Here, we report the first pharmacokinetic data for 5P12-RANTES following single-dose vaginal gel administration in sheep. Aqueous gel formulations containing low (1.24-mg/ml), intermediate (6.18-mg/ml), and high (32.0-mg/ml; suspension-type gel) concentrations of 5P12-RANTES were assessed via rheology, syringeability, and release testing. Following vaginal gel administration to sheep, 5P12-RANTES concentrations were measured in vaginal fluid, vaginal tissue, and serum over a 96-h period. All gels showed non-Newtonian pseudoplastic behavior, with the high-concentration gels exhibiting a greater viscosity and cohesive structure than the intermediate- and low-concentration gels. In release testing, >90% 5P12-RANTES was released from the low- and intermediate-concentration gels after 72 h. For the high-concentration gel, ∼50% 5P12-RANTES was detected, attributed to protein denaturation during lyophilization and/or subsequent solvation of the protein within the gel matrix. In sheep, 5P12-RANTES concentrations in vaginal fluid, vaginal tissue, and serum increased in a dose-dependent manner. The highest concentrations were measured in vaginal fluid (10 to 10 ng/ml), followed by vaginal tissue (10 to 10 ng/ml). Both of these concentration ranges are several orders of magnitude above the reported half-maximal inhibitory concentrations. The lowest concentration was measured in serum (<10 ng/ml). The 5P12-RANTES pharmacokinetic data are similar to those reported previously for other candidate microbicides. These data, coupled with 5P12-RANTES's potency at picomolar concentrations, its strong barrier to resistance, and the full protection that it was observed to provide in a rhesus macaque vaginal challenge model, support the continued development of 5P12-RANTES as a microbicide.

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“…An N-terminally modified variant of CCL5 was developed as a potent CCR5 antagonist and inhibitor of HIV infection [ 155 , 156 ]. Encapsulation of the chemokine in GAG-containing hydrogels was shown to significantly preserve its activity and facilitate its controlled released over the course of a month [ 157 ]. Other therapeutic applications of GAG-based hydrogels have been reported such as their use in sequestering chemokines to promote wound healing [ 158 ].…”

Section: Exploiting Chemokine–gag Interactions For Therapeutic Appmentioning

confidence: 99%

Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System

et al. 2017

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Chemokines have two types of interactions that function cooperatively to control cell migration. Chemokine receptors on migrating cells integrate signals initiated upon chemokine binding to promote cell movement. Interactions with glycosaminoglycans (GAGs) localize chemokines on and near cell surfaces and the extracellular matrix to provide direction to the cell movement. The matrix of interacting chemokine–receptor partners has been known for some time, precise signaling and trafficking properties of many chemokine–receptor pairs have been characterized, and recent structural information has revealed atomic level detail on chemokine–receptor recognition and activation. However, precise knowledge of the interactions of chemokines with GAGs has lagged far behind such that a single paradigm of GAG presentation on surfaces is generally applied to all chemokines. This review summarizes accumulating evidence which suggests that there is a great deal of diversity and specificity in these interactions, that GAG interactions help fine-tune the function of chemokines, and that GAGs have other roles in chemokine biology beyond localization and surface presentation. This suggests that chemokine–GAG interactions add complexity to the already complex functions of the receptors and ligands.

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Using Glycosaminoglycan/Chemokine Interactions for the Long-Term Delivery of 5P12-RANTES in HIV Prevention

Cited by 15 publications

References 38 publications

Providing sustained transgene induction through affinity‐based drug delivery

Providing sustained transgene induction through affinity‐based drug delivery

Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System

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