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Open AccessArticle

Intratumoral Delivery of Doxorubicin on Folate-Conjugated Graphene Oxide by In-Situ Forming Thermo-Sensitive Hydrogel for Breast Cancer Therapy

by Yi Teng Fong 1,2,†, Chih-Hao Chen 2,† and Jyh-Ping Chen 1,2,3,4,*
Department of Chemical and Materials Engineering, Chang Gung University, Taoyuan 33302, Taiwan
Department of Plastic and Reconstructive Surgery and Craniofacial Research Center, Chang Gung Memorial Hospital, Linkou, Kwei-San, Taoyuan 33305, Taiwan
Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Taoyuan 33302, Taiwan
Department of Materials Engineering, Ming Chi University of Technology, Tai-Shan, New Taipei City 24301, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Nanomaterials 2017, 7(11), 388;
Received: 6 October 2017 / Revised: 3 November 2017 / Accepted: 7 November 2017 / Published: 14 November 2017
(This article belongs to the Special Issue Nanocolloids for Nanomedicine and Drug Delivery)
By taking advantage of the pH-sensitive drug release property of graphene oxide (GO) after intracellular uptake, we prepared folic acid (FA)-conjugated GO (GOFA) for targeted delivery of the chemotherapeutic drug doxorubicin (DOX). GOFA-DOX was further encapsulated in an injectable in-situ forming thermo-sensitive hyaluronic acid-chitosan-g-poly(N-isopropylacrylamide) (HACPN) hydrogel for intratumoral delivery of DOX. As the degradation time of HACPN could be extended up to 3 weeks, intratumoral delivery of GOFA-DOX/HACPN could provide controlled and targeted delivery of DOX through slow degradation HACPN and subsequent cellular uptake of released GOFA-DOX by tumor cells through interactions of GOFA with folate receptors on the tumor cell’s surface. GOFA nano-carrier and HACPN hydrogel were first characterized for the physico-chemical properties. The drug loading experiments indicated the best preparation condition of GOFA-DOX was by reacting 0.1 mg GOFA with 2 mg DOX. GOFA-DOX showed pH-responsive drug release with ~5 times more DOX released at pH 5.5 than at pH 7.4 while only limited DOX was released from GOFA-DOX/HACPN at pH 7.4. Intracellular uptake of GOFA by endocytosis and release of DOX from GOFA-DOX in vitro could be confirmed from transmission electron microscopic and confocal laser scanning microscopic analysis with MCF-7 breast cancer cells. The targeting effect of FA was revealed when intracellular uptake of GOFA was blocked by excess FA. This resulted in enhanced in vitro cytotoxicity as revealed from the lower half maximal inhibitory concentration (IC50) value of GOFA-DOX (7.3 μg/mL) compared with that of DOX (32.5 μg/mL) and GO-DOX (10 μg/mL). The flow cytometry analysis indicated higher apoptosis rates for cells treated with GOFA-DOX (30%) compared with DOX (8%) and GO-DOX (11%). Animal studies were carried out with subcutaneously implanted MCF-7 cells in BALB/c nude mice and subject to intratumoral administration of drugs. The relative tumor volumes of control (saline) and GOFA-DOX/HACPN groups at day 21 were 2.17 and 1.79 times that at day 0 with no significant difference. In comparison, the relative tumor volumes of treatment groups at the same time were significantly different at 1.02, 0.67 and 0.48 times for DOX, GOFA-DOX and GOFA-DOX/HACPN groups, respectively. The anti-tumor efficacy was also supported by images from an in vivo imaging system (IVIS) using MCF-7 cells transfected with luciferase (MCF-7/Luc). Furthermore, tissue biopsy examination and blood analysis indicated that intratumoral delivery of DOX using GOFA-DOX/HACPN did not elicit acute toxicity. Taken together, GOFA-DOX/HACPN could be deemed as a safe and efficient intratumoral drug delivery system for breast cancer therapy. View Full-Text
Keywords: thermo-sensitive hydrogel; graphene oxide; folic acid; intratumoral delivery; cancer therapy thermo-sensitive hydrogel; graphene oxide; folic acid; intratumoral delivery; cancer therapy
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MDPI and ACS Style

Fong, Y.T.; Chen, C.-H.; Chen, J.-P. Intratumoral Delivery of Doxorubicin on Folate-Conjugated Graphene Oxide by In-Situ Forming Thermo-Sensitive Hydrogel for Breast Cancer Therapy. Nanomaterials 2017, 7, 388.

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