Erlotinib encapsulated oral chitosan modified lipid nanoparticles for lung cancer

Introduction

Lung cancer is characterized by the abnormal proliferation of cells within the lung which are crucial organs for breathing. It remains a significant global health challenge, ranking highest in terms of cancer-related deaths across the world [1]. Furthermore, lung cancer mortality across all genders exceeds the combined death from breast, colon, and pancreatic cancers [2]. In lung cancer, about 80-85% of cancer is reported for non-small cell lung cancer (NSCLC) [3]. Unhealthy lifestyle choices, occupational hazards, and environmental factors can all contribute to the development of NSCLC [4]. The impacts of these risk factors vary and are influenced by different factors. Smoking emerges as the predominant risk factor associated with the development of NSCLC [5]. Despite efforts, early detection and efficient screening for NSCLC remains elusive, often resulting in diagnosis at advanced stages such as IIIB or IV [6]. Consequently, chemotherapy stands as the primary treatment modality for the treatment of NSCLC [7]. However, most of the anticancer drugs possess hydrophobic properties, leading to poor water solubility, which limits their bioavailability and requires high therapeutic doses [8], [9]. Additionally, conventional delivery methods of chemotherapeutics face challenges such as lack of specificity (resulting in toxicity to healthy cells), fast clearance, and inadequate penetration into tumor sites [10], [11].

Erlotinib (ERT), a quinazoline derivative, is an effective, and one of the frontline drugs used in the NSCLC therapy. Many solid tumors are known to have elevated levels of EGFR, which plays a role in blood vessel formation and the spread of cancer cells. ERT primarily acts through reversible inhibition of EGFR by competitively binding to the ATP binding site of tyrosine kinase I. This action inhibits cell proliferation pathways, ultimately triggering apoptosis and cell death [12]. ERT is categorized as a BCS class II drug candidate. This means it has low solubility and low absorption (around 59%) [13]. Currently, ERT is available as immediate-release tablets under the brand name Tarceva® [14]. Moreover, the development of chemoresistance and side effects like skin rash, diarrhea, and loss of appetite further limit its clinical application [15].

To circumvent the challenges associated with ERT, different nanoparticles-based systems like self-nanoemulsifying drug delivery systems (SNEDDS) [15], poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs) [16], polycaprolactone nanoparticles (PCL-NPs) [17], lipid nanocapsules [18], chitosan nanoparticles [19], and solid lipid nanoparticles (SLNs) [20]. Amidst various formulations, solid lipid nanoparticles have gained significant attention due to their prospects of improving intestinal permeation by enhancing the drug’s solubility. Up on oral administration, SLNs can avoid the hepatic first-pass metabolism by enabling drug absorption through the lymphatic system [21]. After oral administration, SLNs are absorbed via two mechanisms viz transcellular and paracellular transport from the intestine [22]. SLNs are prepared with biodegradable materials and show small particle sizes with excellent homogeneity, good stability in physiological fluids, and controlled release of encapsulated drugs [23], [24]. SLNs can selectively deliver the drug into the tumor tissue by exploiting the tumor environment via a mechanism called the enhanced permeability and retention (EPR) effect and reduce the nonselective distribution of the drug thereby reducing the side effects [25], [26]. Recently, the coating of lipid nanoparticles with mucoadhesive polymer i.e., chitosan gained great attention in enhancing the overall drug absorption. Chitosan, a natural polysaccharide derived from chitin, possesses mucoadhesive properties, meaning it can adhere to the mucosal surfaces of the GIT upon oral administration [27]. The chitosan coating enhances the interaction of nanoparticles with the intestinal mucosa, facilitating improved intestinal permeation across the transepithelial cells. This mucoadhesive property allows for prolonged residence time at the absorption site, increasing the opportunity for drug absorption and uptake into the systemic circulation [28].

D-α-tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble derivative of natural vitamin E (α-tocopherol) formed by esterification with polyethylene glycol (PEG). TPGS possesses amphiphilic properties due to its hydrophilic PEG chain and hydrophobic vitamin E succinate component, allowing it to act effectively as a surfactant. This structure provides excellent biocompatibility and low toxicity, making TPGS suitable for drug delivery applications. Its surfactant nature aids in stabilizing nanoparticle formulations by reducing surface tension and preventing aggregation [29], [30]. Additionally, TPGS is known for its ability to inhibit P-glycoprotein (P-gp), a membrane protein involved in drug efflux, which limits the absorption and bioavailability of many drugs including ERT, particularly in oral delivery [31].

Therefore, to exploit the benefits of TPGS and chitosan coating of lipid nanoparticles, this study was planned to formulate novel TPGS-stabilized ERT-encapsulated chitosan-modified lipid nanoparticles (ERT-CLNPs) for enhanced therapeutic efficacy against lung cancer. To test our hypothesis, ERT-CLNPs were optimized for various formulation parameters, extensively characterized for different physicochemical studies, dissolution profile, stability in gastrointestinal fluids, storage stability, ex-vivo intestinal permeation, and cytotoxicity against lung cancer cells.

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Materials

Erlotinib (ERT; >98% purity), chitosan (MW: 80 kDa, 85% deacetylated with 20 cp viscosity), vitamin E TPGS 5000, and fetal bovine serum (FBS) were purchased from Sigma Aldrich Chemicals, New Delhi, India. Stearic acid (SA) was procured from Thermo Fisher Scientific, Mumbai, India. Poloxamer 188 (PL 188) was provided as a gift sample by BASF Corporation, Mumbai, India. Sodium triphosphate (STPP) was purchased from Sisco Research Laboratories, New Delhi, India.

Najla Altwaijry, Sadaf Jamal Gilani, Ahlam Mansour Sultan, Farhat Fatima, Erlotinib encapsulated oral chitosan modified lipid nanoparticles for lung cancer, Journal of Drug Delivery Science and Technology, 2025, 106612, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.106612.

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Video: Chitosan as a natural excipient