Abstract
Globally, 20%–30% of people are affected by Non‐Alcoholic Fatty Liver Disease (NAFLD). Currently, there is no approved drug for the treatment of NAFLD. It is mostly asymptomatic and is characterized by the accumulation of fat in the liver without excessive alcohol consumption. Capsaicin, a nutraceutical with antilipogenic and anti inflammatory properties, is a promising candidate for NAFLD management. However, its poor bioavailability and potential gastrointestinal irritation limit its clinical utility. To overcome these challenges, capsaicin was encapsulated in a dual delivery system using poly(lactic‐co‐glycolic acid) and bovine serum albumin. This system was developed using nanoprecipitation methods to enhance stability, liver targeting, and therapeutic efficacy of capsaicin. Additionally, the inclusion of albumin helps combating hypoalbuminemia, a condition commonly observed in NAFLD cases. Albumin interacts with hepatic‐specific receptors like the asialoglycoprotein receptor and GP60, which are predominantly expressed on liver cells, enhancing the specificity of albumin‐based nanoparticles for liver uptake. Nanoparticles were optimized for capsaicin loading and tested in HepG2 cellsinduced NAFLD models. Capsaicin nanoparticles significantly reduced intracellular triglycerides, achieving 89% for lipid reduction in a dose‐dependent manner. This dual nanoformulation demonstrates a platform for liver‐targeted capsaicin delivery, addressing limitations of conventional therapies and offering a promising therapeutic approach.
Introduction
The most prevalent chronic liver disease, Non‐alcoholic fatty liver disease (NAFLD), affects approximately 20% 30% of adults with higher rates in industrialized nations.1 It represents the hepatic manifestation of metabolic syndrome and is associated with obesity, hypertension, and type 2 diabetes, in the absence of excessive alcohol consumption.2 While many individuals remain asymptomatic with simple steatosis, a subset progresses to non alcoholic steatohepatitis and, eventually, cirrhosis, followed by liver failure and the necessity for liver transplantation.3
Currently, there are few accepted pharmacological treatments for NAFLD, such as pioglitazone and vitamin E, but they are limited by modest efficacy, safety concerns, and patient‐specific responses.4 This underscores the urgent need for novel therapies targeting the multifactorial pathogenesis of the disease. The primary approach for management involves lifestyle modifications, like physical activity and dietary changes.5 Pharmacological therapies—such as antilipidemic drugs, antioxidants, insulin‐sensitizing agents, and cytoprotective agents—have been explored, but they generally lack specificity and effectiveness, underscoring the need for innovative treatment strategies with improved efficacy.6
Bioactive food constituents have emerged as potential therapeutic agents for various diseases, including NAFLD. Capsaicin (CAP), a phenolic compound found in chilli peppers, has attracted significant attention owing to its diverse pharmacological activities, like antioxidant, anti‐inflammatory anti‐cancer, anti‐diabetes, and antiobesity effects.7 Capsaicin’s role in NAFLD is particularly promising due to its ability to modulate energy balance by inhibiting anabolic pathways and activating catabolic pathways, thus reducing hepatic lipid accumulation. Additionally, capsaicin’s interaction with TRPV1 receptors leads to an analgesic effect through desensitization and depletion of pain‐mediating neuropeptides, making it useful in pain relief treatments.8 Despite its potential, the application of capsaicin in treating NAFLD faces significant challenges, primarily owing to its poor water‐ solubility, leading to poor oral absorption and low bioavailability. Nanocarriers, particularly polymeric nanoparticles like those made from poly (D, L‐lactic‐co‐glycolic acid) (PLGA), have shown promise in enhancing the solubility, stability, and bioavailability of hydrophobic drugs.9 PLGA is approved by the US Food and Drug Administration (FDA) for clinical use in some anti‐cancer drugs due to its biodegradability, controlled release properties, and biocompatibility. Its degradation products, lactic and glycolic acid are natural human metabolites rendering it a safe and effective drug carrier.10 Albumin is FDA approved in management of various liver diseases and can function as targeted therapy owing to albumin specific receptors in liver enhancing endocytosis and to address hypoalbuminemia commonly seen in NAFLD patients.11 Albumin’s reversible binding with endogenous and exogenous ligands, potential to enhance biodistribution, bioavailability, and targeted delivery make it widely used for drug delivery. Marketed formulations like Abraxane® (paclitaxel), Levemir® (myristic acid‐modified insulin), and Victoza® (palmitic acid‐conjugated GLP‐1 agonist) highlight albumin’s ability to extend drug action profiles, improve solubility, and reduce toxicity.12 For liver‐specific targeting, albumin based nanoparticles (NPs) have proven effective in treating hepatic diseases like viral hepatitis, hepatocellular carcinoma (HCC), and liver fibrosis. Examples include galactose‐modified derivatives for DOX and galactosylated bovine serum albumin (BSA) for oridonin, demonstrating enhanced liver targeting, stability, and reduced systemic toxicity. This versatility supports advanced therapeutics, including controlled drug release and reduced off‐target effects, for liver diseases such as NAFLD.13 Additionally, polyvinyl alcohol (PVA) was used to enhance the solubility and dispersibility of the nanoparticles.
This study primarily focuses on developing and optimizing the preparation of dual PLGA and BSA‐loaded capsaicin nanoparticles for treating NAFLD.14 The aim is to enhance capsaicin’s stability, solubility, and bioactivity, providing a novel approach to addressing the urgent need for effective pharmacological therapies for AFLD. The NPs were characterized by measurements of particle size and poly‐dispersity index (PDI), zeta potential, and were further analyzed by using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). The in vitro evaluation was carried out to determine the in vitro cytotoxicity, cellular uptake, and anti‐fat accumulation in oleic acid (OA)‐induced steatosis in human hepatocellular carcinoma (HepG2) cells.15
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Materials and Cell Line
PLGA was purchased from MedChem Express Ltd.. 4′,6‐diamidino‐2‐ phenylindole (DAPI), Dimethylsulfoxide (DMSO), Triton‐X‐100, and dichloromethane (DCM) were purchased from Sisco Research Laboratory. Capsaicin was purchased from Central Drug House Pvt Ltd. Acetonitrile (ACN) was purchased from Thermo Fisher Scientific India Pvt Ltd. Dulbecco’s Modified Eagle’s Medium (DMEM), Fetal bovine serum (FBS), BSA, penicillin−streptomycin antibiotic solution, and phosphate‐buffered saline (PBS) were obtained from HiMedia Laboratories Pvt. Ltd. RIPA lysis buffer was purchased from Thermo Fisher Scientific India Pvt Ltd. Hepatocellular carcinoma (HepG2) cells were obtained from the National Center for Cell Science. The cells were cultured in DMEM supplemented with 10% FBS and 1% antibiotic solution in a humidified incubator maintained at 5% CO2 and 37°C.
Gurneha Kaur, Khushboo Pathania, Kanwaljit Chopra, Sandip V. Pawar, Poly(lactic‐co‐glycolic acid)‐albumin nanoparticles for targeted delivery of capsaicin in alleviating non‐alcoholic fatty liver disease: In vitro study, © 2025 The Author(s). Food Biomacromolecules published by John Wiley & Sons Australia, Ltd on behalf of International Association of Dietetic Nutrition and Safety., Received: 19 January 2025 -Accepted: 26 May 2025, DOI: 10.1002/fob2.70012,University Institute of Pharmaceutical, Sciences, Panjab University, Chandigarh, India
