Pharmaceutical Research

, Volume 33, Issue 1, pp 125–136 | Cite as

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

  • Daniel Carson
  • Yonghou Jiang
  • Kim A. Woodrow
Research Paper



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.


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.


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.


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.


electrospinning high loading HIV programmable release tenofovir 



Percent change in water content


Polymer mass loss percentage








T cell line


Total amount of drug loss


Dulbecco’s Modified Eagle’s Medium


Dimethyl sulfoxide


Dulbecco’s phosphate buffered saline


Differential scanning calorimetry


Fetal bovine serum


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




High performance liquid chromatography


Half maximal inhibition concentration


Power law slope parameter


Sample mass after drying


Sample mass prior to analysis


Amount of drug release at time (t)


Amount of total drug release from the sample




Wet sample mass


Power law expression, release mechanism




Poly-lactic acid


Poly(lactic-co-glycolic) acid


T cell line




Relative luminescence unit


Scanning electron microscopy


Active metabolite of irinotecan


Median tissue culture infective does


Tenofovir disoproxil fumarate


Trifluoroacetic acid




Glass transition temperature


Melting temperature


HeLa cell line



The authors thank the UW-NNIN for assistance with SEM imaging, and T. Kuykendall (UW MSE) for assistance with DSC. Raltegravir and maraviroc samples were purified from their pharmaceutical formulations by M. Ebner, A. Bever and I. Suydam (Seattle University). This work was supported by grants to K.A.W. from the Bill and Melinda Gates Foundation (OPP11110945) and the National Institutes of Health (AI098648, AI112002).

Supplementary material

11095_2015_1769_Fig9_ESM.gif (65 kb)
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)

11095_2015_1769_MOESM1_ESM.tiff (13.9 mb)
High Resolution Image (TIFF 14229 kb)
11095_2015_1769_Fig10_ESM.gif (27 kb)
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)

11095_2015_1769_MOESM2_ESM.tiff (7.7 mb)
High Resolution Image (TIFF 7910 kb)
11095_2015_1769_Fig11_ESM.gif (41 kb)
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)

11095_2015_1769_MOESM3_ESM.tiff (11.4 mb)
High Resolution Image (TIFF 11626 kb)
11095_2015_1769_Fig12_ESM.gif (68 kb)
Supplementary Table 1

(GIF 68 kb)

11095_2015_1769_MOESM4_ESM.tiff (15.4 mb)
High Resolution Image (TIFF 15775 kb)


  1. 1.
    Agarwal S, Wendorff JH, Greiner A. Use of electrospinning technique for biomedical applications. Polymer. 2008;49(26):5603–21.CrossRefGoogle Scholar
  2. 2.
    Li WJ, Laurencin CT, Caterson EJ, Tuan RS, Ko FK. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J Biomed Mater Res A. 2002;60(4):613–21.CrossRefGoogle Scholar
  3. 3.
    Khil MS, Cha DI, Kim HY, Kim IS, Bhattarai N. Electrospun nanofibrous polyurethane membrane as wound dressing. J Biomed Mater Res B. 2003;67B(2):675–9.CrossRefGoogle Scholar
  4. 4.
    Zeng J, Xu X, Chen X, Liang Q, Bian X, Yang L, et al. Biodegradable electrospun fibers for drug delivery. J Control Release. 2003;92(3):227–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Blakney AK, Krogstad EA, Jiang YH, Woodrow KA. Delivery of multipurpose prevention drug combinations from electrospun nanofibers using composite microarchitectures. Int J Nanomedicine. 2014;9:2967–78.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Ball C, Woodrow KA. Electrospun solid dispersions of maraviroc for rapid intravaginal preexposure prophylaxis of HIV. Antimicrob Agents Chemother. 2014;58(8):4855–65.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Huang C, Soenen SJ, Gulck EV, Vanham G, Rejman J, Calenbergh SV, et al. Electrospun cellulose acetate phthalate fibers for semen induced anti-HIV vaginal drug delivery. Biomaterials. 2012;33(3):962–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Vasita R, Katti DS. Nanofibers and their applications in tissue engineering. Int J Nanomedicine. 2006;1(1):15–30.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Goh YF, Shakir I, Hussain R. Electrospun fibers for tissue engineering, drug delivery, and wound dressing. J Mater Sci. 2013;48(8):3027–54.CrossRefGoogle Scholar
  10. 10.
    Chew SY, Wen J, Yim EKF, Leong KW. Sustained release of proteins from electrospun biodegradable fibers. Biomacromolecules. 2005;6(4):2017–24.PubMedCrossRefGoogle Scholar
  11. 11.
    Xie J, Wang CH. Electrospun Micro- and nanofibers for sustained delivery of paclitaxel to treat C6 glioma in vitro. Pharm Res. 2006;23(8):1817–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Yohe ST, Colson YL, Grinstaff MW. Superhydrophobic materials for tunable drug release: using displacement of air to control delivery rates. J Am Chem Soc. 2012;134(4):2016–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim K, Luu YK, Chang C, Fang D, Hsiao BS, Chu B, et al. Incorporation and controlled release of a hydrophilic antibiotic using poly(lactide-co-glycolide)-based electrospun nanofibrous scaffolds. J Control Release. 2004;98(1):47–56.PubMedCrossRefGoogle Scholar
  14. 14.
    Zeng J, Yang L, Liang Q, Zhang X, Guan H, Xu X, et al. Influence of the drug compatibility with polymer solution on the release kinetics of electropun fiber formulation. J Control Release. 2005;105(1–2):43–51.PubMedCrossRefGoogle Scholar
  15. 15.
    Sohrabi A, Shaibani PM, Etayash H, Kaur K, Thundat T. Sustained drug release and antibacterial activity of ampicillin incorporated poly(methyl methacrylate). Polymer. 2013;54(11):2699–705.CrossRefGoogle Scholar
  16. 16.
    Hsu YH, Chen DW, Tai CD, Chou YC, Liu SJ, Ueng SW, et al. Biodegradable drug-eluting nanofiber-enveloping implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies. Int J Nanomedicine. 2014;9:4347–55.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Valarezo E, Tammaro L, Malagon O, Gonzalez S, Armijos C, Vittoria V. Fabrication and characterization of Poly(lactic acid)/Poly(e-caprolactone) blend electrospun fibers loaded with amoxicillin for tunable delivering. J Nanosci Nanotechnol. 2014;14:1–7.CrossRefGoogle Scholar
  18. 18.
    Reise M, Wyrwa R, Muller U, Zylinski M, Volpel A, Schnabelrauch M, et al. Release of metronidazole from electrospun poly(L-lactide-co-D/L-lactide) fibers for local periodontitis treatment. Dent Mater. 2012;28(2):179–88.PubMedCrossRefGoogle Scholar
  19. 19.
    Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel, Switz). 2011;3(3):1377–97.CrossRefGoogle Scholar
  20. 20.
    Fredenber S, Wahlgren M, Reslow M, Axelsson A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems—a review. Int J Pharm. 2011;415(1–2):34–52.CrossRefGoogle Scholar
  21. 21.
    McDonald PF, Lyons JG, Geever LM, Higginbotham CL. In vitro degradation and drug release from polymer blends based on poly(DL-lactide), poly(L-lactide-glycolide) and poly(e-caprolactone). J Mater Sci. 2010;45(5):1284–92.CrossRefGoogle Scholar
  22. 22.
    Lao L, Venkatraman S, Peppas N. Modeling of drug release from biodegradable polymer blends. Eur J Pharm Biopharm. 2008;70(3):796–803.PubMedCrossRefGoogle Scholar
  23. 23.
    Ritger PL, Peppas NA. A simple equation for the description of solute release I. fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5(1):23–36.CrossRefGoogle Scholar
  24. 24.
    Ball C, Krogstad EA, Chaowanachan T, Woodrow KA. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS One. 2012;7(11):1–14.CrossRefGoogle Scholar
  25. 25.
    Krogstad EA, Woodrow KA. Manufacturing scale-up of electrospun poly(vinyl alcohol) fibers containing tenofovir for vaginal delivery. Int J Pharm. 2014;475(1–2):282–91.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Notari S, Tommasi C, Nicastri E, Bellagamba R, Tempestilli M, Pucillo LP, et al. Simultaneous determination of maraviroc and raltegravir in human plasma by HPLC-UV. IUBMB Life. 2009;61(4):470–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Lyu S, Sparer R, Hobot C, Dang K. Adjusting drug diffusivity using miscible polymer blends. J Control Release. 2005;102(3):679–87.PubMedCrossRefGoogle Scholar
  28. 28.
    Yu D, Branford-White C, White K, Li XL, Zhu LM. Dissolution improvement of electrospun nanofiber-based solid dispersion for acetaminophen. AAPS PharmSciTech. 2010;11(2):809–17.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Chen SC, Huang XB, Cai XM, Lu J, Yuan J, Shen J. The influence of fiber diameter of electrospun poly(lactic acid) on drug delivery. Fibers Polym. 2012;13(9):1120–5.CrossRefGoogle Scholar
  30. 30.
    Labet M, Thielemans W. Synthesis of polycaprolactone: a review. Chem Soc Rev. 2009;38(12):3484–504.PubMedCrossRefGoogle Scholar
  31. 31.
    You Y, Youk JH, Lee SW, Byung-Moo M, Lee SJ, Park WH. Preparation of porous ultrafine PGA fibers via selective dissolution of electrospun PGA/PLA blend fibers. Mater Lett. 2006;60(6):757–60.CrossRefGoogle Scholar
  32. 32.
    Tan LP, Hidayat A, Lao LL, Quah LF. Release of hydrophilic drug from biodegradable polymer blends. J Biomater Sci Polym Ed. 2009;20(10):1381–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Del Rev. 2001;48(2–3):139–57.CrossRefGoogle Scholar
  34. 34.
    Natu MV, de Sousa HC, Gil MH. Effects of drug solubility, state and loading on controlled release in bicomponent electrospun fibers. Int J Pharm. 2010;397(1–2):50–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Langer RS, Wiser DL, et al. Medical applications of controlled release. Boca Raton: CRC Press, Inc.; 1984.Google Scholar
  36. 36.
    Peppas NA, Brannon-Peppas L. Water diffusion sorption in amorphous macromolecular systems and foods. J Food Eng. 1994;22(1–4):189–210.CrossRefGoogle Scholar
  37. 37.
    Blasi P, Schoubben A, Giovagnoli S, Perioli L, Ricci M, Rossi C. Ketoprofen poly(lactide-co-glycolide) physical interaction. AAPS PharmSciTech. 2007;8(2):E78–85.PubMedCentralCrossRefGoogle Scholar
  38. 38.
    Johnson TJ, Gupta KM, Fabian J, Albright TH, Kiser PF. Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir. Eur J Pharm Sci. 2010;39(4):203–12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of BioengineeringUniversity of WashingtonSeattleUSA

Personalised recommendations