Development of a combinational drug delivery system for synergistic lung cancer treatment

Abstract

Proteins are a key component in cell regulation while playing various cell roles. Among their many roles, transporter functions are considered a vital part of cell functionality. Thus, the incorporation of proteins in pharmaceutical drug design has increased over the years. The principal benefits of protein therapeutics are the specificity to complex functions, low tendency to side effects, and high tolerance in the body. These benefits are mainly due to the body's wide variety of protein production, so it is not detected as a foreign agent. Some therapeutic formulations are composed of protein-drug conjugates and protein-based drug delivery systems (including drug encapsulation) to improve treatment for targeted tissues. In the case of cancer therapy, several protein-based nanoparticles are FDA-approved and show excellent pharmacological results in delivering their drug component. Unfortunately, cancer tissue can develop resistance to anticancer drugs delivered. Thereby, that tissue becomes tolerant to cancer treatment.<br /> <br /> Doxorubicin is one of the most common anticancer drugs reported to induce chemoresistance in cancer cells. The development of drug resistance is a cellular response which uses differential gene expression to enable adaptation and survival of the cell to diverse threatening environmental agents. Otherwise, betulinic acid, a pentacyclic triterpene (plant-derived compound), has shown great cytotoxic activity against different cancer types. In chapter 3, the term Chemoresistance will be introduced, and some key genes involved in cancer therapy resistance meanwhile mentioning some drug delivery systems that may improve the efficiency of chemotherapy. Chapter 4 investigates a protein-based drug delivery system (DDS) nanoparticles from serum albumin (BSA) as the drug's carrier combining two compounds. Due to their synergistic cytotoxicity demonstrated against non-small cell lung carcinoma A549 cells. The chemotherapy drug doxorubicin (Dox) and the triterpene betulinic acid (BeA) were encapsulated using an oil-water-like micro-emulsion method. In addition, the BSA (Dox+BeA) DDS demonstrated cytotoxic activity after 24h incubation. The mechanism of action studies confirmed S-phase cell cycle arrest, ATM-dependent DNA damage, multi-caspase pathways activation, and a reduction in the epidermal growth factor receptor (EGFR) expression compared to the drugs alone.