Physical Characterization and Cellular Testing of Polymeric Micelle Formulations for Intravenous Delivery of Hydrophobic Anticancer Drugs

Abstract

Colorectal cancer ranks amongst the top three types of cancer diagnosed in the United States and is the second most common cause of cancer death. There are several drugs approved for the treatment of colon cancer. However, one of the more commonly used treatments, immune checkpoint inhibitors, are only effective in around 15% of patients diagnosed with metastatic colon cancer. Furthermore, many anti-cancer drugs specific to colon cancer are hydrophobic and thus have poor water solubility. Therefore, there is a need for a delivery formulation that is water soluble so that the drug can be introduced to the blood stream. With these requirements in mind, the overarching goal of this project is to develop a delivery system using micelles that are water soluble, and that can hold hydrophobic anti-cancer drugs. To achieve this goal, there are a few characteristics of the micelles that need to be ascertained to determine their suitability in tumor treatment. These include critical micelle concentration (CMC), encapsulation efficiency, size and cytotoxicity. These characteristics denote the concentration at which micelles form, how much drug they can hold, their diameter, and whether they are toxic to cells. Previous research done for this project investigated a new hydrophobic drug with which to treat colon cancer, as well as a micelle formulation to facilitate the delivery of this drug. The new drug is 15-deoxy, ∆12,14-PMJ2 and was originally investigated for use against melanoma cancer but has shown promising results for treating colon cancer. The first micelle formulation used was a 1:5 ratio of DSPE:TPGS, where DSPE is a polyethylene glycol conjugated phosphatidylethanolamine and TPGS is a polyethylene glycol derivative of α-tocopherol (vitamin E). These micelles exhibited promising characteristics such as a low CMC, a high encapsulation efficiency when loaded with drug, and an appropriate size for nanoparticles used in cancer treatment (between ≈ 10-100 nm). However, it was discovered that this formulation was cytotoxic towards cancer cells, so the project pivoted to investigate pluronic F127 micelles as an alternative delivery system. Pluronic is the trade name for triblock copolymers composed of a central hydrophobic chain of polypropylene oxide (PPO) which is between two hydrophilic chains of polyethylene oxide (PEO); the F127 designation denotes the structure PEO100PPO65PEO100. These micelles were also found to have a low CMC, although not as low as DSPE:TPGS, a high encapsulation efficiency, and an appropriate size for tumor treatment. In addition to these findings, the micelles also showed little to no cytotoxicity towards cancer cells. Thus, pluronic F127 micelles are now the primary candidate for the delivery of PMJ for future research projects.