Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer
Introduction
Multidrug resistance (MDR) is the most frequent phenomenon by which cancer cells elude chemotherapy, and is a main obstacle for the successful chemotherapy of cervical and breast cancer. One of the well-known mechanisms of MDR is the over-expression of adenosine triphosphate-binding cassette (ABC) transmembrance transporter protein P-glycoprotein (MDR1/P-gp) [1], [2]. Due to their ability to pump drugs out of the cells, these proteins lead to reductions in the intracellular drug concentration and decreased cytotoxicity [3]. Regulation of P-gp and apoptotic proteins has become an area of study for researchers, and attempts are under way to target these MDR cells to make them susceptible to therapy [4], [5].
Nanomedicine provides an excellent platform for rational drug delivery of anticancer agents to tumors upon systemic administration and circumvents the problem of MDR [6]. Some of the best structures for drug delivery systems are micelles, liposomes, polymeric nanoparticles and solid lipid nanoparticles (SLN) [7], [8], [9], [10], [11], [12]. SLN, the first generation of solid lipid carrier systems in a nanometer range, were introduced as an alternative to liposomes. SLN are well tolerated in living systems since they are aqueous colloidal dispersions whose matrix includes physiological and solid biodegradable lipids. The advantages of SLN are as follows: possibility of controlled drug release and drug targeting, no bio-toxicity of the carrier, fair bioavailability and drug incorporation for hydrophobic drugs [13], [14]. In addition, surface modifications of SLN with targeting moiety enable these SLN to increase their selectivity for tumor cellular binding and internalization [15].
Active targeting can improve the distribution of SLN inside the tumor vasculature and to MDR cells [16]. Hyaluronic acid (HA), a high molecular linear glycosaminoglycan, is an attractive polymer in the field of active targeting anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic and non-immunogenic [17], [18]. In particular, the frequent over-expression of HA receptors CD44 and CD168 (RHAMM) on many types of tumors opens new avenues for targeting. Therefore, we developed HA-coated SLN for tumor-targeted delivery.
In order to overcome drug resistance, P-gp inhibitors such as Cremophor EL, Tween80, D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS), Pluronic and chitosan derivatives, are commonly used. Among these P-gp inhibitors, Pluronic has been proven to be the most effective one [19], [20], [21]. Thus, the novel Pluronic and 1,2-distearoyl-sn-glycero-3-phosphatidel-ehanolamine (DSPE) conjugate was synthesized. The amphipathic property makes it easier to construct SLN. In particular, the DSPE terminal (the lipophilic terminal) is inserted into the core of SLN, and the Pluronic terminal (the hydrophilic terminal) is covered outside of SLN.
Paclitaxel (PTX) is one of the most important chemotherapeutic agents used to treat various types of cancer such as cervical and breast cancer [22]. It is also a P-gp substrate, and prone to multidrug resistance during the long term chemotherapy [23]. In this report, HA decorated, PTX loaded, pluronic P85 SLN were designed to reverse drug-resistance of P-gp over-expressing human cervix adenocarcinoma cell line (HeLa/PTX cells), and human breast cancer cell line (MCF-7/PTX cells). Firstly, Pluronic P85-DSPE conjugate (P85-DSPE) was synthesized. PTX loaded, P85-DSPE cationic SLN (PTX-P85-SLN) were prepared by the hot homogenization technique. Then, an aqueous solution of HA was added to form HA decorated PTX/P85-DSPE SLN (HA-PTX-P85-SLN). The ability of SLN to reverse drug resistance was evaluated both in HeLa/PTX (or MCF-7/PTX) in vitro culture model and HeLa/PTX (or MCF-7/PTX) mice model.
Section snippets
Chemicals and reagents
Paclitaxel was provided by Zhejiang Hisun Pharmaceutical Co., Ltd (Zhejiang, China). Docetaxel (DTX, internal standard, IS) was obtained from Qilu Pharmaceutical Co., Ltd (Shandong, China). Pluronic 85 (P85) was generously provided by BASF (Shanghai, China). 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) was purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China). Glyceryl monostearate (GMS) was purchased from Aladdin Industrial Corporation (Shanghai, China).
Synthesis and characterization of P85-DSPE
To evaluate the inhibition efficiency of P85/solid lipid nanoparticles (SLN) in overcoming the MDR of MCF-7, the P85-DSPE conjugate was synthesized by an amide coupling reaction between the amines of DSPE and the CDI-P85, which was obtained by activating the hydroxyl groups of P85 with CDI (Fig. 2).
Determination of HA modified ratio
Various HA-PTX-P85-SLN were prepared by changing the amount of HA solution to that of PTX-P85-SLN (1:1, 2:1, 4:1, 6:1, 8:1, 10:1 and 12:1; w/w). Fig. 3A shows the effect of HA coating on mean
Discussion
In this work, we have utilized the ionic interaction between cationic DOTAP SLN and anionic HA to form lipid-polymer hybrid SLN (HA-P85-SLN) and examined their efficacy as delivery vehicles for anti-tumor chemotherapeutic agents in vitro and in vivo to overcome MDR.
Extensive experimental evidence demonstrated the important role of HA-CD44 interaction in cell proliferation and tumor growth [27], [39]. Taking advantage of this interaction, the design of HA-modified nanocarriers has been
Conclusion
In the present study, a novel HA-P85-SLN delivery system was designed and compared with free PTX. In vitro cell viability studies using cervical and breast cancer cells revealed that HA-PTX-P85-SLN had highest cytotoxicity than other formulations. In vivo animal evaluation (pharmacokinetics and tissue distribution, and anti-tumor study) demonstrated that HA-P85-SLN prolonged MRT in circulation, and increased PTX accumulation in HeLa/PTX tumor tissue. Therefore, HA-P85-SLN could be a potential
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