Pectin co-functionalized dual layered solid lipid nanoparticle made by soluble curcumin for the targeted potential treatment of colorectal cancer
Introduction
Generally, among all cancer types, colorectal cancer (CRC) is considered as a major type and reported to be the second and third most prevalent cancer in women and men, respectively, aged 60–75 years (Rawla, Sunkara, & Barsouk, 2019). More so, CRC is among the leading cause of death worldwide particularly in developed countries which account for 65 % of the total CRC cases. Colon polyps, long-standing colic ulcers, and heredity are the possible risk factors of CRC (Hall & Ruutiainen, 2018).
Most anticancer drugs may develop toxicity in the body for several reasons. Synthetic or semisynthetic drugs may have various side effects such as bone marrow depression, alopecia, extreme fatigue, loss of self-esteem, loss of immunity, and a remarkable decline in WBC count. The insoluble properties of anticancer drugs lead to accumulation at the absorption site, and this may develop toxicity (Nurgali, Jagoe, & Abalo, 2018).
Numerous studies on CMN have shown that this lipophilic polyphenol is the active component present in turmeric which is obtained from the rhizomes of the Curcuma longa (Akram et al., 2010; Sachin, Kailash, & Gyana, 2016) and is commonly used in India and China as traditional herbal medicine. CMN has various anticancer activities, but its weak pharmacokinetics limited its therapeutic application (Ireson et al., 2001). In order to overcome these demerits, many delivery systems, including solid dispersion (SD), cyclodextrin complexation, phospholipid complexes, liposomal approach, and the use of nanocrystals and polymeric nanoparticles, have been developed. However, these frameworks continue to have issues such as restricted physical stability, difficulty in drug loading, and the possible toxicity of the excipients (Bansal, Goel, Aqil, Vadhanam, & Gupta, 2001). The basic technique of SD to improve the insoluble drug of the blend having drug and carrier was completely converted from liquid/semisolid to solid state. Finally, the solid was pulverized in maximum cases and then suitably sieved (Seo, Han, Chun, & Choi, 2012).
Solid lipid nanoparticles (SLN) have considerable fascination in recent years due toassociated advantages when compared to other colloidal systems. Some of these advantages include improved physical stability and protecting the drug from metabolism by enzyme, sustaining the drug release, better drug encapsulation and biocompatibility, ease of production, and ease of sterilization. Additionally, SLNs provide both long term stability and biological compatibility with the solid drug and solid lipid carriers (Rosiaux, Jannin, Hughes, & Marchaud, 2014). Although many researchers have investigated CMN enclosed SLN formulation, interestingly the present study on SC loaded lipid frame using natural biopolymers against CRC has not been studied.
Pectin and skimmed milk powder (SMP) are natural biopolymers from food sources, which are obtained from the plant (polysaccharide) and the key protein (casein) from milk, respectively. SMP is recognized as an amphiphilic properties and acts as an emulsifying agent by adsorbing in oil/water interface (lipid surface), whereas pectin has been extensively studied for acid protection in the gastro intestinal (GI) environment (Wang, Ma, Lei, & Luo, 2016). The complexation amongst SMP and pectin is anticipated to the aid of superficial “electro-deposition” process brought about by modifying the pH by thermal application.
The pharma and biotech industries are seeking techniques to increase the potential and to reduce the toxicity of chemotherapeutic agents. The soluble form of anti-cancer drug has extensive attention in recent decades than native form. The present investigation provides the efficiency of co-functionalized pectin in the enhancement the solubility and pharmacokinetic stability of CMN in various GI conditions that makes a potential targeted action on colon. Moreover, natural source of drug and biopolymers used in this investigation can make an ideal system for the target delivery of anti-cancer drug with low cost treatment for CRC without toxicity even at high doses (Muthu, Kavitha, Ruckmani, & Shanmuganathan, 2019).
This paper explored the use of SC loaded into solid lipid frame with the aim of improving its solubility and stabilizing SLNs in various GI conditions. Natural biopolymer (SMP and pectin) coating are shown to restrict the degradation of drug at various pH condition (Nguyen, Alund, Hiorth, Kjoniksen, & Smistad, 2011). This investigation aims to understand the potential cytotoxicity, cellular uptake, and better bioavailability of CMN through the oral route at colon.
The purpose of the present research is to investigate (i) the utilization of SC for the preparation of SLN, (ii) molecular docking of DL-SLN (iii) optimization of the variable response for the preparation of SC loaded SLN (SC-SLN) (iv) exposure of SLN by in vitro dissolution and its physicochemical characterization, (v) upgrading SLN in its hostile action against colon cancer and enhancing both regression activity in SW480 cells, (vi) investigation of targeting potential and in vivo toxicity.
Section snippets
Materials
Curcumin (CMN, Diferuloylmethane; > 99 % of purity from SRL Pvt. Ltd, India), Poloxamer 407, the copolymer of ethylene oxide/propylene oxide with a molecular weight of 102.13 g/mol (PXM), Pectin (beta-d-galacturonic acid) from BASF Corporation, India, Sucrose (saccharose, with a molecular weight of 342.3 g/mol) from S.D. Fine Chem. Pvt. Ltd, India, Skimmed milk powder (SMP, Aavin, Tamil Nadu Co-operates Milk Product Producers, India), and Tween 80 (Polyoxyethylene sorbitan monooleate), Span 80
Molecular docking
In this computer simulation, the molecular dynamics study of DL-SLN was simulated to characterize SLN formation and the interaction between the CMN-PXM-SC-Pectin at molecular level. This simulation and interaction analyses were used to provide a more comprehensive snapshot of what happens in the interior of the DL-SLN system. Additionally, the thermodynamical stability of the CMN inside the pectin/CP/PXM system was also obtained in a time-dependent manner (Seelan et al., 2016). From the result
Conclusion
The results obtained in this study showed that SLN can enhance the cytotoxicity and stability of curcumin, and reduces associated toxicity. Specific target delivery was achieved by coating with the layers of pectin and skimmed milk powder. The anticancer potential of the prepared DL-SLN was evaluated on human colorectal adenocarcinoma cell lines of SW480. The colon targeting potential of the DL-SLN by the organ distribution estimation has shown that the maximium amount of CMN has reached the
CRediT authorship contribution statement
J. Muthu Mohamed: Conceptualization, Investigation, Methodology, Formal analysis, Writing - original draft. Ali Alqahtani: Writing - original draft, Formal analysis, Data curation. Fazil Ahmad: Software, Writing - review & editing. V. Krishnaraju: Validation, Writing - review & editing. K. Kalpana: Writing - review & editing.
Acknowledgements
The authors are thankful to the National Centre for Alternatives to Animal Experiments (NCAAE), Bharathidasan University, India, for providing facilities to perform cell line studies. Also thankful to King Institute of Preventive Medicine and Research, Chennai, India, for given facilities to carry out zebra fish toxicity and western blot analysis, etc.
References (86)
- et al.
Colon targeted beads loaded with pterostilbene: Formulation, Optimization, Characterization and in vivo evaluation
Journal of the Saudi Pharmaceutical Society
(2019) - et al.
Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake
European Journal of Pharmaceutics and Biopharmaceutics
(2017) - et al.
Preparation and in vitro evaluation of vaginal formulations including siRNA and paclitaxel-loaded SLNs for cervical Cancer
European Journal of Pharmaceutics and Biopharmaceutics
(2016) - et al.
E-cadherin expression is silenced by DNA methylation in cervical cancer cell lines and tumours
European Journal of Cancer
(2003) - et al.
Transcriptional regulation of actin and myosin genes during differentiation of a mouse muscle cell line
Differentiation
(1990) - et al.
Preparation and evaluation of zinc-pectin-chitosan composite particles for drug delivery to the colon: Role of chitosan in modifying in vitro and in vivo drug release
International Journal of Pharmaceutics
(2011) - et al.
In vitro characterization and in vivo toxicity study of repaglinide loaded poly (methyl methacrylate) nanoparticles
International Journal of Pharmaceutics
(2010) - et al.
Colorectal Cancer: Imaging conundrums
Surgical Oncology Clinics of North America
(2018) - et al.
Romidepsin induces cell cycle arrest, apoptosis, histone hyperacetylation and reduces matrix metalloproteinases 2 and 9 expression in bortezomib sensitized non-small cell lung cancer cells
Biomedecine & Pharmacotherapy
(2014) - et al.
Formulation of solid lipid nanoparticles (SLN): The value of different alkyl polyglucoside surfactants
International Journal of Pharmaceutics
(2014)