Pharmaceutical Research

, Volume 33, Issue 1, pp 125–136

Tunable Release of Multiclass Anti-HIV Drugs that are Water-Soluble and Loaded at High Drug Content in Polyester Blended Electrospun Fibers

Research Paper

DOI: 10.1007/s11095-015-1769-0

Cite this article as:
Carson, D., Jiang, Y. & Woodrow, K.A. Pharm Res (2016) 33: 125. doi:10.1007/s11095-015-1769-0

Abstract

Objectives

Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters.

Methods

Drug-loaded fibers were fabricated by electrospinning ratios of PCL and PLGA. Fiber morphology was imaged by SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay.

Results

We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 h or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro.

Conclusions

These data suggest that we were able to overcome current limitations associated with sustained release of small molecule hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications.

KEY WORDS

electrospinning high loading HIV programmable release tenofovir 

ABBREVIATIONS

%CH2O

Percent change in water content

%MLpolymer

Polymer mass loss percentage

ACN

Acetonitrile

ARV

Antiretroviral

AZT

Azidothymidine

CEMx174

T cell line

DLtotal

Total amount of drug loss

DMEM

Dulbecco’s Modified Eagle’s Medium

DMSO

Dimethyl sulfoxide

DPBS

Dulbecco’s phosphate buffered saline

DSC

Differential scanning calorimetry

FBS

Fetal bovine serum

HEPES

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HFIP

Hexafluoroisopropanol

HPLC

High performance liquid chromatography

IC50

Half maximal inhibition concentration

k

Power law slope parameter

Mdry

Sample mass after drying

Mpre

Sample mass prior to analysis

Mt

Amount of drug release at time (t)

Mtotal

Amount of total drug release from the sample

MVC

Maraviroc

Mwet

Wet sample mass

n

Power law expression, release mechanism

PCL

Poly-caprolactone

PLA

Poly-lactic acid

PLGA

Poly(lactic-co-glycolic) acid

PM-1

T cell line

RAL

Raltegravir

RLU

Relative luminescence unit

SEM

Scanning electron microscopy

SN-38

Active metabolite of irinotecan

TCID50

Median tissue culture infective does

TDF

Tenofovir disoproxil fumarate

TFA

Trifluoroacetic acid

TFV

Tenofovir

Tg

Glass transition temperature

Tm

Melting temperature

TZM-bL

HeLa cell line

Supplementary material

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Supplementary Figure 1

Standard curves and chromatograms of TFV, AZT, MVC, and RAL in DMSO, used for evaluation of encapsulation efficiency. Traces of blank PCL/PLGA fibers dissolved in DMSO and DMSO blank are also included in each method to demonstrate the absence of polymer influence on detection of drug. (a) TFV detection: 1–100 μgmL−1, R2 = 0.99999, LLOQ = 20 ng, retention time = ~2.3 min. (b) AZT detection: 1–100 μgmL−1, R2 = 0.99856, LLOQ = 10 ng, retention time = ~3.5 min. (c) MVC detection: 1–100 μgmL−1, R2 = 0.99982, LLOQ = 20 ng, retention time = ~8.7 min. (d) RAL detection: 1–100 μgmL−1, R2 = 0.99996, LLOQ = 20 ng, retention time = ~3.9 min. (GIF 64 kb)

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Supplementary Figure 2

Cytotoxicity assay of four PCL/PLGA fiber formulations after 10 days in solution. TFV concentration in solution amongst fiber formulations and polymer concentrations displayed a range of 4.3 × 102–1.1 × 106 nM. TZM-bl cell viability is ~100% for all tested blends at tested concentrations. Cytotoxicity was also tested in two other T cell lines, which showed similar results to TZM-bl cells (data not shown). This results supports in vitro viral inhibition is due to released TFV and not a result of polymer toxicity. (GIF 26 kb)

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Supplementary Figure 3

In vitro sink condition release of TFV compared to TFV release as calculated by HIV inhibition in vitro. Viral activity was tested on four PCL/PLGA blends with 15 wt% TFV at 24, 48, 120, and 240 h. IC50 values were calculated and compared to free TFV. %TFV release was calculated using the aforementioned comparison. The results displayed similar release profiles between as TFV release in sink conditions and TFV release based on viral activity. (GIF 40 kb)

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Supplementary Table 1

(GIF 68 kb)

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High Resolution Image (TIFF 15775 kb)

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of BioengineeringUniversity of WashingtonSeattleUSA