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Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices.

Gunaseelan S, Gallay PA, Bobardt MD, Dezzutti CS, Esch T, Maskiewicz R - Pharm. Res. (2012)

Bottom Line: Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo.Durations of release ranging from several days to several months were readily achieved.Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350, USA.

ABSTRACT

Purpose: Use of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.

Methods: Tenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.

Results: Drug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.

Conclusion: Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

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Related in: MedlinePlus

Effect of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) incorporated into PF-11 matrix pellets on HIV infection in ectocervical explants. HIV-1 infection is monitored over 21 days by HIV-1 p24gag protein detected in the basolateral culture supernatant. Endpoint immunohistochemistry was performed to confirm infection. The presence of infected cells (red deposits) is indicative of p24-positive cells. The data presented are the median ±95% confidence interval of three independent tissues and representative immunohistochemistry figures.
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Fig6: Effect of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) incorporated into PF-11 matrix pellets on HIV infection in ectocervical explants. HIV-1 infection is monitored over 21 days by HIV-1 p24gag protein detected in the basolateral culture supernatant. Endpoint immunohistochemistry was performed to confirm infection. The presence of infected cells (red deposits) is indicative of p24-positive cells. The data presented are the median ±95% confidence interval of three independent tissues and representative immunohistochemistry figures.

Mentions: To be a therapeutically relevant drug delivery system, especially in the context of extended duration microbicide delivery, drug loaded subliming matrices should provide prolonged and continuous antiviral activities. A clinically relevant ex vivo model for sexual infection examining residual infectivity subsequent to multiple HIV challenge of human extocervical explants, was used to demonstrate this capability. A result typical of multiple challenge is for HIV-1 p24 concentrations to initially rise, then decrease upon challenge cessation, and then continue to drop to a steady value indicating the extent of residual infection (Fig. 6). The antiviral activity of microbicide candidates is determined by whether the tissues are protected against infection, relative to untreated controls. An advantage to using ectocervical explants for product testing is that appropriate HIV-1 target cells are present in the appropriate ratio. Using this model (23,24), we determined whether a given subliming solid is capable of delivering sufficient amounts of TDF or FTC to the tissue and prevent HIV-1 residual infection after multiple viral challenge. Over the course of the 21 day culture period, viral challenge occurred every 3 to 4 days over the first 10 days of culture (4 independent exposures to HIV-1) with treatment entailing either a single bolus administration of TDF or FTC in solution prior to the first challenge, or continuous release of TDF or FTC from PF-11 matrix discs during and subsequent to challenges. After virus challenges ceased, HIV-1 p24 levels decreased in the control explants, in those treated with either TDF or FTC in solution, and those treated with placebo matrices, to a constant level of 3.8 log10 pg/mL by day 17 of culture (Fig. 6).Fig. 6


Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices.

Gunaseelan S, Gallay PA, Bobardt MD, Dezzutti CS, Esch T, Maskiewicz R - Pharm. Res. (2012)

Effect of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) incorporated into PF-11 matrix pellets on HIV infection in ectocervical explants. HIV-1 infection is monitored over 21 days by HIV-1 p24gag protein detected in the basolateral culture supernatant. Endpoint immunohistochemistry was performed to confirm infection. The presence of infected cells (red deposits) is indicative of p24-positive cells. The data presented are the median ±95% confidence interval of three independent tissues and representative immunohistochemistry figures.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3473190&req=5

Fig6: Effect of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) incorporated into PF-11 matrix pellets on HIV infection in ectocervical explants. HIV-1 infection is monitored over 21 days by HIV-1 p24gag protein detected in the basolateral culture supernatant. Endpoint immunohistochemistry was performed to confirm infection. The presence of infected cells (red deposits) is indicative of p24-positive cells. The data presented are the median ±95% confidence interval of three independent tissues and representative immunohistochemistry figures.
Mentions: To be a therapeutically relevant drug delivery system, especially in the context of extended duration microbicide delivery, drug loaded subliming matrices should provide prolonged and continuous antiviral activities. A clinically relevant ex vivo model for sexual infection examining residual infectivity subsequent to multiple HIV challenge of human extocervical explants, was used to demonstrate this capability. A result typical of multiple challenge is for HIV-1 p24 concentrations to initially rise, then decrease upon challenge cessation, and then continue to drop to a steady value indicating the extent of residual infection (Fig. 6). The antiviral activity of microbicide candidates is determined by whether the tissues are protected against infection, relative to untreated controls. An advantage to using ectocervical explants for product testing is that appropriate HIV-1 target cells are present in the appropriate ratio. Using this model (23,24), we determined whether a given subliming solid is capable of delivering sufficient amounts of TDF or FTC to the tissue and prevent HIV-1 residual infection after multiple viral challenge. Over the course of the 21 day culture period, viral challenge occurred every 3 to 4 days over the first 10 days of culture (4 independent exposures to HIV-1) with treatment entailing either a single bolus administration of TDF or FTC in solution prior to the first challenge, or continuous release of TDF or FTC from PF-11 matrix discs during and subsequent to challenges. After virus challenges ceased, HIV-1 p24 levels decreased in the control explants, in those treated with either TDF or FTC in solution, and those treated with placebo matrices, to a constant level of 3.8 log10 pg/mL by day 17 of culture (Fig. 6).Fig. 6

Bottom Line: Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo.Durations of release ranging from several days to several months were readily achieved.Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350, USA.

ABSTRACT

Purpose: Use of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.

Methods: Tenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.

Results: Drug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.

Conclusion: Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

Show MeSH
Related in: MedlinePlus