International Journal of Biological Macromolecules
Tween 80-modified hyaluronic acid-ss-curcumin micelles for targeting glioma: Synthesis, characterization and their in vitro evaluation
Graphical abstract
Introduction
More than 70,000 people are diagnosed with primary brain tumors in the world each year, of which about 17% suffer from glioma [1]. It has aroused widespread concerns due to short survival time and high mortality in the glioma treatment. The rapid development in the field of nanotechnology based drug delivery vehicles possessing target specificity and effective release of drugs has attracted attentions [2]. Among them, polymeric drug delivery systems have become a promising platform for cancer treatment due to following advantages: 1) increased drug solubility; 2) improved bioavailability and altered tissue distribution; 3) enhanced the drug accumulation in the tumor tissues by the Enhanced Permeability and Retention (EPR) effect; 4) reduced side effects in normal tissues [3]. Nowadays, different types of polymeric drug delivery systems have been developed, such as polymer-drug conjugates [4], polymeric micelles [5] and polymeric gels [6]. Notably, conjugation of drug with polymers (polymeric prodrugs) does not only improve stability and solubility of the drug, but can retain the drug and efficiently prevent the rapid drug release, therefore prolonging the circulation time and improving the in vivo drug efficacy [3].
In order to develop polymer-drug conjugates, a variety of synthetic and natural polymers have been conjugated with hydrophobic drugs. Hyaluronic acid (HA), a linear polysaccharide consisting of repeating units of N-acetyl-d-glucamine and d-glucuronic acid, is a ubiquitous component of the extracellular matrix and can be used as a hydrophilic backbone [7,8]. Moreover, HA can specifically bind to the CD44 receptors expressed in many cancer cells (such as breast, ovarian, gliomas and colon) [9]. Therefore, HA has become the focus of some anticancer drug targeting studies, and application of several HA-based systems in chemotherapy has been demonstrated [10]. Curcumin (CUR), a low molecular weight polyphenolic compound found in the spice turmeric (Curcuma longa), is well known for its significant antitumor activity against a variety of cancers including brain glioma [11]. Despite the treatment benefits, therapeutic efficacy of CUR has not been extensively exploited due to its low stability and poor aqueous solubility at physiological pH [12]. Studies have shown that CUR, as a hydrophobic group, can be linked to HA via an ester bond to form an amphiphilic conjugate without affecting the pharmacological activity of CUR [13]. Manju and Sreenivasan have found that conjugating CUR with HA enhanced its stability and aqueous solubility [14]. Hu et al. have developed a HA-CUR polymeric pro-drug which showed enhanced cellular internalization of the HA-CUR polymeric pro-drug compared to free CUR in CD44 receptor expressing cells [15].
However, owing to the presence of blood brain barrier (BBB), drug delivery to brain is a major challenge in the treatment of glioma [16]. Tight junctions of BBB formed by the brain microvascular endothelial cells limit paracellular transport of molecules (ions, peptides, amino acids and drugs) [17]. Thus, transport across BBB plays a key role in the treatment of gliomas. A number of studies have revealed that polysorbate 80 (or Tween 80) can allow the adsorption of apolipoprotein E (apoE) onto the nanoparticle surface, and these nanoparticles could be transport into the brain through the low density lipoprotein (LDL) receptor-mediated endocytosis [18,19]. Thus, Tween 80 is considered as an ideal coating material for brain-targeted nanoparticles. Meng et al. reported that nanostructured lipid carriers modified with polysorbate 80 (PS80-NLCs) showed a significantly higher affinity for bEnd.3 cells (1.56 times greater than NLCs) and could permeate BBB effectively and accumulate in the brain (2.38 folds greater than NLCs) [20].
In recent years, rapid release of drug at tumor site triggered by the internal stimulus (reductive potential/pH/lysosomal enzymes) aroused widespread interest from researchers [21,22]. It is noteworthy that reduction-sensitive nanoparticles can dissociate and release drugs at high reducing conditions [23]. Studies have demonstrated that the intracellular levels of natural reducing agent, glutathione (GSH), in cancerous cells are significantly higher (about 1–11 mM) than that of plasma levels (about 1–10 μM) [3]. Disulfide bonds (-ss-) can be cleaved into thiols via GSH, therefore, many research groups have used the disulfide-linked reduction-sensitive systems for anticancer drug delivery. Enhanced cytotoxicity in A2780/T cells of D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX conjugate (TPGS-ss-PTX) compared with TPGS-C-C-PTX group (without -ss-) has been revealed by Bao et al. [24].
In this study, Tween 80-modified redox-sensitive micelles based on hyaluronic acid-ss-curcumin (HSC) conjugate were designed as a dual-targeting carrier for the treatment of brain glioma (Fig. 1). Insensitive HA-CUR (HC) conjugates (structurally analogous to HSC) lacking the disulfide bond in linkages were also synthesized for comparison. These conjugates were confirmed by 1H NMR and FTIR. The degree of substitution (DS) of CUR, critical micelle concentration (CMC) and redox-sensitivity of conjugates were also evaluated. These conjugates could self-assemble into micelles in aqueous medium. Thereafter, CUR can be further loaded into their hydrophobic cavity (the micelles named as CUR-HSC and CUR-HC micelles, respectively). Subsequently, their surfaces were coated with Tween 80 to ultimately improve brain drug delivery (the micelles named as CUR-THSC and CUR-THC, respectively). Physicochemical properties of different micelles including particle size, zeta potential, polydispersity index (PDI), drug entrapment efficiency (EE), drug loading (DL), transmission electron microscopy (TEM), and X-ray diffraction (XRD) were studied. Cytotoxicities of different micelles were investigated in G422 cells.
Section snippets
Materials
HA (MW = 10 kDa, purity, 94.76%) was purchased from C. P. Freda Pharmaceutical Co. Ltd. (Shandong, China). CUR (purity, 98%) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) were purchased from Aladdin Reagent Co., Ltd. (Shanghai, China). Cystamine dihydrochloride (CyH) and N-hydroxysuccinimide (NHS) were purchased from J&K Technology Co., Ltd. (Beijing, China). Polysorbate 80 (Tween 80), succinic anhydride (SA) and 4-dimethylaminopyridine (DMAP) were purchased from Sinopharm Chemical
Synthesis and characterization of HSC and HC conjugates
In this study, low molecular weight HA (10 kDa) was chosen to synthesize HSC and HC conjugates. HSC conjugate was prepared via amide reaction of the amino groups of HA-ss-NH2 and the carboxyl groups of CUR-COOH, while HC conjugate was synthesized by the direct esterification reaction of HA with CUR. The disulfide bond content of HA-ss-NH2 was 0.131 μmoL/g. The DS of CUR in HSC and HC conjugates were determined to be 6.23% and 1.36%, respectively.
Fig. 2A shows the synthetic scheme and the
Conclusion
In summary, we have successfully developed and optimized brain targeted micelles with redox-sensitivity as a carrier of CUR for the treatment of glioma. The redox-sensitive HSC conjugate was synthesized through conjugation of HA and CUR to the amino groups of CyH. This amphiphilic conjugate could self-assemble into micellar particles in an aqueous environment to further encapsulate the hydrophobic drug CUR which was further modified with Tween 80 to facilitate penetration of the blood-brain
Acknowledgment
This work has been supported by the National Natural Science Foundation of China (Program No. 81503027), and College Students Innovation Project for the R&D of Novel Drugs (Program No. J1310032).
References (47)
- et al.
PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma
Biomaterials
(2016) - et al.
Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: an attractive tool for drug delivery
J. Control. Release
(2007) - et al.
Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release
J. Control. Release
(2013) - et al.
Self-reinforced endocytoses of smart polypeptide nanogels for “on-demand” drug delivery
J. Control. Release
(2013) - et al.
PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo
Biomaterials
(2011) - et al.
Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma
Eur. J. Med. Chem.
(2016) - et al.
Curcumin: the story so far
Eur. J. Cancer
(2005) - et al.
Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability
J. Colloid Interface Sci.
(2011) - et al.
CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage
Carbohydr. Polym.
(2018) - et al.
The blood-brain barrier in Alzheimer's disease: novel therapeutic targets and nanodrug delivery
Int. Rev. Neurobiol.
(2012)
Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art
Eur. J. Pharm. Biopharm.
Specific role of polysorbate 80 coating on the targeting of nanoparticles to the brain
Biomaterials
Design and evaluation of lipoprotein resembling curcumin-encapsulated protein-free nanostructured lipid carrier for brain targeting
Int. J. Pharm.
Thermo-and pH-responsive copolymers based on PLGA-PEG-PLGA and poly (l-histidine): synthesis and in vitro characterization of copolymer micelles
Acta Biomater.
Reduction-sensitive polymers and bioconjugates for biomedical applications
Biomaterials
The effect of the molecular weight of hyaluronic acid on the physicochemical characterization of hyaluronic acid-curcumin conjugates and in vitro evaluation in glioma cells
Colloids Surf. B: Biointerfaces
Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel
Biomaterials
Conjugation of curcumin onto alginate enhances aqueous solubility and stability of curcumin
Carbohydr. Polym.
A study of the binding of CI Mordant Red 3 with bovine serum albumin using fluorescence spectroscopy
Dyes Pigments
Hyaluronic acid/chitosan nanoparticles for delivery of curcuminoid and its in vitro evaluation in glioma cells
Int. J. Biol. Macromol.
Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer
Biomaterials
Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin
Eur. J. Pharm. Sci.
Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies
Int. J. Pharm.
Cited by (43)
Engineering nanoprobes for magnetic resonance imaging of brain diseases
2024, Chemical Engineering JournalPhycocyanin/lysozyme nanocomplexes to stabilize Pickering emulsions for fucoxanthin encapsulation
2023, Food Research InternationalBerberine-loaded zein/hyaluronic acid composite nanoparticles for efficient brain uptake to alleviate neuro-degeneration in the pilocarpine model of epilepsy
2023, European Journal of Pharmaceutics and BiopharmaceuticsDelivery of quercetin for breast cancer and targeting potentiation via hyaluronic nano-micelles
2023, International Journal of Biological MacromoleculesDual-targeted enzyme-sensitive hyaluronic acid nanogels loading paclitaxel for the therapy of breast cancer
2022, Carbohydrate PolymersCitation Excerpt :After 24 h, the obtained solution was centrifuged (12,000 rpm, 10 min), and the supernatant was dialyzed (membrane MW cut-off 3500 Da) against ethanol/water (1:2, v/v) initially for 24 h and then against deionized water for 48 h. Finally, the product (MHA) was collected by lyophilization. Cholesteryl-2-aminoethylcarbamate (CHOL-NH2) was synthesized as per literature (Miao et al., 2013; Tian et al., 2018). Briefly, 3.7 mL EDA was dropped into a stirred solution of CHOL in anhydrous dichloromethane (10 mL, 50 mg/mL).
Enhancing autophagy in Alzheimer's disease through drug repositioning
2022, Pharmacology and Therapeutics