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.
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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
References
Agarwal S, Wendorff JH, Greiner A. Use of electrospinning technique for biomedical applications. Polymer. 2008;49(26):5603–21.
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.
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.
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.
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.
Ball C, Woodrow KA. Electrospun solid dispersions of maraviroc for rapid intravaginal preexposure prophylaxis of HIV. Antimicrob Agents Chemother. 2014;58(8):4855–65.
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.
Vasita R, Katti DS. Nanofibers and their applications in tissue engineering. Int J Nanomedicine. 2006;1(1):15–30.
Goh YF, Shakir I, Hussain R. Electrospun fibers for tissue engineering, drug delivery, and wound dressing. J Mater Sci. 2013;48(8):3027–54.
Chew SY, Wen J, Yim EKF, Leong KW. Sustained release of proteins from electrospun biodegradable fibers. Biomacromolecules. 2005;6(4):2017–24.
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.
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.
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.
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.
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.
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.
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.
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.
Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel, Switz). 2011;3(3):1377–97.
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.
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.
Lao L, Venkatraman S, Peppas N. Modeling of drug release from biodegradable polymer blends. Eur J Pharm Biopharm. 2008;70(3):796–803.
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.
Ball C, Krogstad EA, Chaowanachan T, Woodrow KA. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS One. 2012;7(11):1–14.
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.
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.
Lyu S, Sparer R, Hobot C, Dang K. Adjusting drug diffusivity using miscible polymer blends. J Control Release. 2005;102(3):679–87.
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.
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.
Labet M, Thielemans W. Synthesis of polycaprolactone: a review. Chem Soc Rev. 2009;38(12):3484–504.
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.
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.
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.
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.
Langer RS, Wiser DL, et al. Medical applications of controlled release. Boca Raton: CRC Press, Inc.; 1984.
Peppas NA, Brannon-Peppas L. Water diffusion sorption in amorphous macromolecular systems and foods. J Food Eng. 1994;22(1–4):189–210.
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.
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.
ACKNOWLEDGMENTS AND DISCLOSURE
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).
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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)
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)
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)
Supplementary Table 1
(GIF 68 kb)
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Carson, D., Jiang, Y. & Woodrow, K.A. Tunable Release of Multiclass Anti-HIV Drugs that are Water-Soluble and Loaded at High Drug Content in Polyester Blended Electrospun Fibers. Pharm Res 33, 125–136 (2016). https://doi.org/10.1007/s11095-015-1769-0
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DOI: https://doi.org/10.1007/s11095-015-1769-0