A Quality by Design Paradigm for Albumin‑Based Nanoparticles: Formulation Optimization and Enhancement of the Antitumor Activity

Abstract

Purpose: Albumin nanoparticles are promising carriers for therapeutic agents, owing to their biocompatibility, safety, and versatility in fabrication. The formulation of albumin nanoparticles is highly affected by many product and process variables, resulting in a great variation in these nanoparticles. The aim of this work was to formulate and optimize albumin nanoparticles loaded with silymarin, as a model drug with low bioavailability, for the treatment of hepatocellular carcinoma, using quality by design (QbD) approach.

Methods: A thorough risk assessment for albumin nanoparticles formulation was developed and a complete quality product profile was defined using the QbD approach. A D-optimal design was used to optimize the amount of albumin and drug, which significantly affected the particle size (PS) and the entrapment efficiency (EE%), which was further tested on hepatocellular carcinoma.

Results: A design space was constructed, with an optimized formula showing a PS of 135 nm, a polydispersity index (PDI) of 0.09, an EE% of 88%, and a zeta potential of − 12.5 mV. The optimized formula (O1) with spherical particles, showed an extended-release rate as compared to free silymarin. Moreover, a pronounced anti-proliferation activity of O1 was observed on human hepatocellular carcinoma cell line HepG2 than the free drug. The flow cytometric analysis of the cell cycle showed a significant suppression of the S-phase after treating the HepG2 cell with O1, but not with free silymarin.

Conclusion: Thus, a detailed QbD study has been conducted, with deep product and process understanding, and resulted in a successful formulation of silymarin albumin nanoparticles for the suppression of hepatocellular carcinoma.