Preparation and characterization of an injectable thermosensitive hydrogel for simultaneous delivery of paclitaxel and doxorubicin

Mahboubeh Rezazadeh, Vajihe Akbari, Elham Amuaghae, Jaber Emami


In the current study, we aimed to develop a novel injectable thermosensitive hydrogel for simultaneous intra-tumoral administration of paclitaxel (PTX) and doxorubicin hydrochloride (DOX). At first, mixed micelles composed of Pluronic F127 and α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was loaded with PTX and their physicochemical properties including particle size, zeta potential, drug loading content, entrapment efficiency, and the drug release were investigated in details. In the second step, the optimized PTX-loaded micelles prepared in the first step were incorporated into the thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel containing fixed amount of DOX. Gel formation temperature, rheological properties, injectability, degradation rates of the hydrogel, and the release rate of PTX and DOX from the hydrogel were examined. The mean particle sizes and zeta potentials of the PTX-loaded micelles were 157.5 ± 20.1 nm and -9.6 ± 1.1 mV, respectively. The entrapment efficiency of the formulation was about 51%. The hydrogel containing PTX-loaded micelles and DOX existed as a solution with low viscosity at 4 °C converted to a semisolid upon increasing the temperature to 35 °C. DOX was completely released from the hydrogel within 12 h, while 40-80% of PTX could be released from the different formulations during 3 days. This novel thermosensitive hydrogel prepared in the current study could be efficiently used for co-delivery of PTX and DOX in solid tumor types. 


Paclitaxel; Doxorubicin hydrochloride; Co-delivery; Thermosensitive hydrogel.

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Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MH, Wilcken N. Combination versus sequential single agent chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. 2013:18(12). DOI: 10.1002/14651858.CD008792.

Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. N Engl J Med. 2011;364(11):985-987

Wang H, Zhao Y, Wu Y, Hu YL, Nan KH, Nie GJ, et al. Enhanced anti-tumor efficacy by co delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011;32(32):8281-8290.

Xiao H, Song H, Yang Q, Cai H, Qi R, Yan L, et al. A prodrug strategy to deliver cisplatin (IV) and paclitaxel in nanomicelles to improve efficacy and tolerance, Biomaterials. 2012;33(27):6507-6519.

Gupte A, Ciftci K. Formulation and characterization of Paclitaxel, 5-FU and Paclitaxel + 5-FU microspheres. Int J Pharm. 2004;276(1-2):93-106.

Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine. 2008;3(6):761-776.

Taratula O, Kuzmov A, Shah M, Garbuzenko OB, Minko T. Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. J Control Release. 2013;171(3):349-357.

Zhang C, Qu G, Sun Y, Wu X, Yao Z, Guo Q, et al. Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. Biomaterials. 2008:29(9):1233-1241.

Qu G, Yao Z, Zhang C, Wu X, Ping Q. PEG conjugated N-octyl-O-sulfate chitosan micelles for delivery of paclitaxel: In vitro characterization and in vivo evaluation. Eur J Pharm Sci. 2009:37(2): 98-105.

Gardner ER, Dahut W, Figg WD. Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment. J Chromatogr B Analyt Technol Biomed Life Sci. 2008: 862(1-2):213-218.

Wolinsky JB, Colson YL, Grinstaff MW. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release. 2012;159:14-26.

Dhanikula A.B, Panchagnula R. Development and characterization of biodegradable chitosan films for local delivery of paclitaxel. AAPS J. 2004:6(3):e27.

Elstad NL, Fowers KD. OncoGel (ReGel/paclitaxel)-clinical applications for a novel paclitaxel delivery system Adv Drug Deliv Rev. 2009;61(10):785-794.

Bajaj G, Kim MR, Mohammed SI, Yeo Y. Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors. J Control Release. 2012:158(3):386-392.

Westpha M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke P, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003:5(2):79-88.

Pradilla G, Wang PP, Gabikian P, Li K, Magee CA, Walter KA, et al. Local intracerebral administration of Paclitaxel with the Paclimer® delivery system: toxicity study in a canine model. J Neurooncol. 2006;76(2):131-138.

Colson YL, Liu R, Southard EB, Schulz MD, Wade JE, Griset AP, et al. The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis, Biomaterials. 2011;32(3):832-840.

Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2012;64:18-23.

Ahmed F, Pakunlu RI, Brannan A, Bates F, Minko T, Discher D. Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. J Control Release. 2006;116(2):150-158.

Al-Abd AM, Hong KY, Song SC, Kuh HJ. Pharmacokinetics of doxorubicin after intratumoral injection using a thermosensitive hydrogel in tumor-bearing mice. J Control Release. 2010;142:101-107.

Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003;21(4):588-592.

Mavroudis D, Kouroussis Ch, Kakolyris S, Agelaki S, Kalbakis K, Androulakis N, et al. Phase I study of paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) administered every 2 weeks in patients with advanced solid tumors. Oncology. 2002;62(3):216-222.

Zhang Z, Tan S, Feng SS. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials. 2012;33(19):4889-4906.

Emami J, Rezazadeh M, Rostami M, Hassanzadeh F, Sadeghi H, Mostafavi A, et al. Co-delivery of paclitaxel and α-tocopherol succinate by novel chitosan-based polymeric micelles for improving micellar stability and efficacious combination therapy. Drug Dev Ind Pharm. 2015;41(7):1137-1147.

Youk HJ, Lee E, Choi MK, Lee YJ, Chung JH, Kim SH, et al. Enhanced anticancer efficacy of alph-tocopheryl succinate by conjugation with polyethylene glycol. J Control Release. 2005;107:43-52.

Lee Y, Chung HJ, Yeo S, Ahn CH, Lee H, Messersmith PB, et al. Thermo-sensitive injectable, and tissue adhesive sol-gel transition hyaluronic acid/pluronic composite hydrogel prepared from bio-inspired catechol-thiol reaction. Soft Matter. 2010;6:977-983.

Yang Y, Wang J, Zhang X, Lu W, Zhang Q. A novel mixed micelle gel with thermo-sensitive property for local delivery of docetaxel. J Control Release. 2009;135(2):175-182.

Kim MR, Park TG. Temperature-responsive and degradable hyaluronic acid/pluronic composite hydrogels for controlled release of human growth hormons. J control Release. 2002;80(1-3):69-77.

Emami J, Rezazadeh M, Mashayekhi M, Rostami M, Jahanian-Najafabadi A. A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis, characterization, cytotoxicity, and pharmacokinetic evaluation. Drug Dev Ind Pharm. 2017:1-12. DOI: 10.1080/03639045.2017.1411940.

Rungaseevijitprapa W, Bodmeier R. Injectability of biodegradable in situ forming microparticle systems (ISM). Eru J Pharm Sci. 2009;36(4-5):524-531.

Ke XY, Lin Ng VW, Gao SJ, Tong YW, Hedrick JL, YangYY. Co-delivery of thioridazine and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells. Biomaterials. 2014;35(3):1096-1108.

Patel NR, Rathi A, Mongayt D, Torchilin VP. Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes. Int J Pharm. 2011;416:296-299.

Lv S, Tang Z, Li M, Lin J, Song W, Liu H, et al. Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials. 2014;35(23):6118-6129.

Ma Y, Fan X, Li L. pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel. Carbohydr Polym. 2016;137:19-29.

Li Q, Lv S, Tang Z, Liu M, Zhang D, Yang Y, et al. A co-delivery system based on paclitaxel grafted mPEG-b-PLG loaded with doxorubicin: Preparation, in vitro and in vivo evaluation. Int J Pharm. 2014:471(1-2):412-420.

Ruel-Gariepy E, Shive M, Bichara A, Berrada M, Le Garrec D, Chenite A, et al. A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel. Eur J Pharm Biopharm. 2004;57:53-63.


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