Transferrin functionalized nanostructured lipid carriers for targeting Rivastigmine and Resveratrol to Alzheimer's disease: Synthesis, in vitro characterization and brain uptake analysis

The management of Alzheimer’s disease (AD) remains challenging owing to its complex pathophysiology and blood-brain barrier (BBB) restrictions. A rationally designed combination drug multi-target strategy has emerged as a promising approach for AD management. Considering the lipophilic nature of BBB and the need to embed dual drugs- Rivastigmine hydrogen tartrate and Resveratrol, nanostructured lipid carriers (NLCs) were used as drug delivery vehicle. NLCs were formulated by water/oil/water (w/o/w) double emulsion method and optimized using central composite design. HPLC method for simultaneous determination of drugs was developed and validated. To target the overexpressed Transferrin (TF) receptors, NLCs were surface functionalized with TF by covalent coupling employing carbodiimide chemistry.

The success of conjugation was ascertained by Zeta potential, FTIR and TEM and the Bradford assay which estimated the conjugation efficiency of 47.52 ± 3.2%. A particle size of <100 nm was obtained which is favourable for brain delivery. Sustained release of drugs from nanoparticles was obtained, where TF-NLCs demonstrated a significantly slow release compared to NLCs. The functional stability and biocompatibility of the nanosystems was ensured by DPPH assay and hemolysis test, respectively. The confocal laser scanning microscopy (CLSM) revealed significantly higher (∼1.7 folds) brain uptake of TF-NLCs compared to NLCs in vivo following intraperitoneal administration. Dual drugs loaded TF functionalized NLCs demonstrated favourable in vitro and in vivo attributes for efficient brain targeting and hence AD management.

Materials

Rivastigmine Hydrogen Tartrate (RHT) was obtained as a generous gift sample from Dr. Reddy’s Laboratories, Hyderabad. Resveratrol was purchased from TCI chemicals. Solid and liquid lipids were supplied by Gattefosse India Pvt. Ltd. Capmul® MCM C8, Captex® 300 and Captex® 355 were provided by Abitec Corporation India. Oleic acid, Stearic acid, Cremophor® ELP, Poloxamer 188, Poloxamer 407, D-ɑ-tocopheryl polyethylene glycol succinate (TPGS)

Dhara Jain, Nazeer Hasan, Sobiya Zafar, Jitesh Thakur, Kashif Haider, Suhel Parvez, Farhan Jalees Ahmad, Transferrin functionalized nanostructured lipid carriers for targeting Rivastigmine and Resveratrol to Alzheimer’s disease: Synthesis, in vitro characterization and brain uptake analysis, Journal of Drug Delivery Science and Technology, 2023, 104555, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2023.104555.

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