Abstract
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.
Highlights
In recent years, an effective cancer treatment platform has always been the focus of developing advanced drug delivery systems based on different nano-sized drug carriers [1,2]
With an aim to improve antitumor therapeutic effects and to decrease the side effects of DOX, we have successfully demonstrated that GOFA nano-carrier could conjugate with DOX and be encapsulated in hyaluronic acid-chitosan-g-poly(N-isopropylacrylamide) (HACPN) to enhance its cytotoxicity toward MCF-7 breast cells in vitro
We have confirmed the synthesis of the nano-sized anticancer drug carrier GOFA, the intracellular uptake of GOFA by endocytosis and the specific targeting effect of GOFA toward MCF-7 breast cancer cells
Summary
An effective cancer treatment platform has always been the focus of developing advanced drug delivery systems based on different nano-sized drug carriers [1,2]. Modifying an anticancer drug nano-carrier, such as GO, with FA could enhance its ability to be recognized and its intracellular uptake efficiency by cancer cells through ligand-mediated targeting drug delivery [16,17]. Ndaenloimveatreyriaslsy2s0t1e7m, 7s, 3h8a8ve the potential to enable the loading and release of insoluble anticancer d3rouf g24s through in-situ forming thermo-sensitive hydrogel This drug delivery system can deliver anticancer drugs locally to the tumor site, leading to low dose requirements and reduce multiple drug dadrumgisntishtrroautigohn icny-cslietus, fworhmicihngcothueldrmroe-dsuecnesitoirveelhimydinroatgeela. This was supported by quantitative analysis of the amount of FA conjugated to GO, which is 98.2 μg FA/mg GOFA with 92.8% loading efficacy
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