DESIGN OF EXPERIMENTS (DOE) ASSISTED CUBOSOMAL DRUG DELIVERY SYSTEMS FOR CANCER THERAPY: FORMULATION STRATEGIES, OPTIMIZATION, AND PHARMACEUTICAL APPLICATIONS

Cancer remains a major global health challenge, creating a need for advanced drug delivery systems capable of improving therapeutic efficacy while minimizing systemic toxicity. Cubosomes, a class of lipid-based nanocarriers with bicontinuous cubic liquid crystalline structures, have gained significant attention in cancer therapy due to their high drug-loading capacity, biocompatibility, controlled release behavior, and ability to encapsulate both hydrophilic and hydrophobic drugs. These nanostructures enhance drug solubility, stability, cellular uptake, and tumor targeting, thereby improving the therapeutic performance of anticancer agents. However, optimization of cubosomal formulations is challenging because of the complex interactions among formulation variables and processing parameters. Design of Experiments (DOE) has emerged as an effective statistical and systematic approach for the development and optimization of pharmaceutical nanoformulations. DOE enables simultaneous evaluation of multiple variables, identification of critical factors, reduction in experimental runs, and generation of robust and reproducible formulations. Several DOE models, including factorial design, Box–Behnken design, central composite design, and response surface methodology, have been widely employed for cubosome optimization. This review highlights the fundamentals, composition, preparation techniques, characterization methods, and pharmaceutical applications of cubosomes in cancer therapy. Special emphasis is placed on DOE-assisted optimization strategies, critical quality attributes, and recent advancements in targeted and stimuli-responsive cubosomal systems. Additionally, Quality by Design (QbD), regulatory perspectives, current challenges, and future opportunities in cubosome-mediated cancer therapy are discussed. DOE-assisted cubosomal systems represent a promising platform for developing effective and targeted anticancer therapies with improved clinical outcomes.