Targeted delivery of curcumin in breast cancer cells via hyaluronic acid modified mesoporous silica nanoparticle to enhance anticancer efficiency
Graphical abstract
Introduction
In the recent decades, the development of nanotechnology in nanomedicine field has facilitated us to search advanced practises of drug delivery systems (DDSs) [1][37][39]. These nanomaterial based delivery systems not only get over the lack of delivery but additionally enrich the effectiveness of therapy (for instance, improving the bioavailability of some naturally occurring antioxidant molecules like curcumin) [2]. Mesoporous silica nanoparticle (MSN) has been stated to hold significant benefits like easy synthesis, high chemical and mechanical stability, large surface area, tuneable pore sizes, facile surface functionalization, good endocytotic behaviour, biocompatibility, etc. over the organic drug carriers [3]. However, it has been established that MSN exhibits no significant toxicity which is a common problem with organic nanoparticle based DDS. Several reports showed that curcumin can be loaded in different nanomaterials including cyclodextrins, chitosan nanoparticles, liposomes, etc. [[4], [5], [6]][38]. In addition to the above DDS, MSN can also be studied as a potential drug carrier system for curcumin for its diversity. Additionally, targeted delivery may similarly enhance the bioavailability of curcumin into cancer cells and diminish the adverse effect towards healthy cells.
For effective cancer treatments, targeted delivery is very much needed because most of the currently used anticancer drugs dispense all over the body and may cause detrimental effect to healthy cells [7]. To minimize the side effects, scientists aim to specifically increase the concentration of anticancer drug at the target sites. Nanoparticles have a tendency to mount up at the tumor sites, commonly described as the enriched permeability and retention (EPR) effect [8], as the diameters (≤100 nm) of MSNs are controllable as nano-carriers they have the potential to progress ongoing cancer treatments. The targeting capacity of MSN, facilitated by the abundant silanol groups (Si−OH), is mainly important for cancer therapy [9]. The targeting moieties include specific ligands (such as hyaluronic acid, folic acid, 3-carboxy benzoic acid, mannose and arginine–glycine–aspartate (RGD), antibodies, peptides etc.). The strong targeting action along with the EPR effect additionally enhances the cellular intake of MSNs in cancerous cells, focusing to a significant progression in anti-cancer therapy [10]. Hyaluronic acid (HA) is a biocompatible and biodegradable glycosaminoglycan. This non-immunomodulatory component of the extracellular matrix is crucial for appropriate growth of cell, organs’ structural stability and organization of tissue [11]. HA co-operates with numerous cell surface receptors, including RHAMM (receptor for hyaluronan-mediated motility, CD168 linking with wound healing and cancer), Toll-like receptors-2 and -4 (recognizing hyaluronan oligomers in dendritic cells during inflammatory events), and HARE (HA receptor for endocytosis) [12]. Moreover, evidence showed that numerous types of cancer cells overexpress CD44 like HA receptors which can be employed to upsurge drug/cargo build-up specifically in cancer cells with CD44 over-expression [13]. Moreover, HA modification also facilitates cell entry via the HA receptor mediated endocytosis pathway [14]. This novel strategy can, therefore, be very useful for cancer targeting treatments. Nevertheless, few studies are available on HA modified MSN so far. So in this study, we have examined whether HA modified MSN (HA-MSN) could increase the bioavailability of curcumin and enhance the targeting efficiency of MSN itself. For this purpose we have firstly synthesized HA-MSN and characterised it thoroughly (by SEM, TEM, DLS, FTIR, XRD, UV–vis spectra). Then we have taken two various breast cancer cell lines, such as MCF-7 and MDA-MB-231, the latter having abundant HA receptors. Results indicated that the anti-cancer activity of curcumin was much more pronounced in the second cell line. This is probably due to the more abundance of HA receptors in these cells than the other one. Results also revealed that the anticancer effect was associated with ROS over production, loss of mitochondrial membrane potential (MMP) and subsequent mitochondria dependent path of apoptosis. When the effect of this particular DDS was extrapolated to in vivo system we have got similar kind of results. Firstly, this DDS was found to be non-toxic to the animals at the experimental doses. MSN-HA could also increase the anti-cancer efficacy of curcumin as shown by the tumour regression assay. This novel nanoformulation might, therefore, become a very potent delivery system for curcumin.
Section snippets
Chemicals
Tetraethyl-orthosilicate (TEOS), ethanol and cetryltrimethylammonium bromide (CTAB) were procured from Merck. Formaldehyde, methanol, ammonia solutions (25 % v/v) and methyl thiazolyl diphenyl tetrazolium bromide (MTT) were bought from SRL. (3-Aminopropyl) triethoxysilane (APTES) and rhodamine isothiocyanate were obtained from Sigma. Curcumin, FBS and all culture media were purchased from HIMEDIA and Gibco, respectively. Annexin V apoptosis detection kit, anti-Bax primary antibodies and
Synthesis and characterization of hyaluronic acid functionalized mesoporous silica nanoparticles loaded with curcumin
In this study, at first, HA tagged mesoporous silica nanoparticles (MSN) loaded with curcumin (MSN-HA-C) was synthesized following the method described elsewhere [17]. The drug loading content (DLC) and drug entrapment efficiency (DEE) were 16.45 % and 21.09 %, respectively in MSN-C. DLC and DEE were 14.76 % and 18.5 %, respectively (Table 1). Then MSNs were characterized by several techniques. We have also performed FE-SEM and TEM analysis which revealed the size, shape as well as surface
Conclusion
Our study indicated that hyaluronic acid functionalised MSN can be an effective nanoparticle-based drug delivery systems for the treatment of breast cancer cells. MDA-MB-231, being a triple negative breast cancer cell, is very aggressive in terms of both immortality and invasiveness. Both of the problems can be taken care of by this particular drug delivery system carrying curcumin as cargo molecule. This NP showed its efficacy in both augmenting apoptosis and retarding cancer cell migration.
CRediT authorship contribution statement
Shatadal Ghosh: Conceptualization, Methodology, Software, Data curation, Writing - original draft, Visualization, Investigation, Validation, Writing - review & editing, Formal analysis. Sayanta Dutta: Visualization, Investigation, Software. Abhijit Sarkar: Visualization, Investigation. Mousumi Kundu: Visualization, Investigation. Parames C. Sil: Conceptualization, Methodology, Software, Data curation, Writing - original draft, Supervision, Writing - review & editing, Funding acquisition,
Declaration of Competing Interest
The authors declared no conflict of interest
Acknowledgements
The authors acknowledge DST, UGC and Bose Institute for providing financial assistance.
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