Development of Targeted, Enzyme-activated Nano- Conjugates for Hepatic Cancer Therapy
Hepatocellular carcinoma (HCC) is the 5th most commonly-occurring cancer and the 2nd highest cause for cancer-related deaths worldwide. The current treatment strategy is the direct injection of a chemotherapeutic drug (e.g. doxorubicin; DOX) into the hepatic artery, through a process called hepatic arterial infusion (HAI). Unfortunately, HAI is severely hindered by limited therapeutic efficacy against the tumor and high systemic toxicity to surrounding organs (e.g. the heart).
This thesis focuses on the development of a targeted, nanoparticle-based drug delivery system aimed to improve the clinical treatment of HCC. In particular, we employ generation 5 (G5) poly(amido amine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands attached to the surface through a poly(ethylene glycol) (PEG) brush. DOX is attached to the G5 surface through two different enzyme-sensitive linkages, L3 or L4, to achieve controllable release of the drug inside hepatic cancer cells. The combination of NAcGal-PEG targeting branches with either L3- or L4-DOX linkages led to the development of P1 and P2 particles, respectively.
- In Part 1, we discuss the development of these particles and measure their ability to target and kill hepatic cancer cells in vitro.
- In Part 2, we investigate whether P1 and P2 particles can improve antitumor activity and mitigate cardiotoxicity in tumor-bearing mice, compared to the free drug.
- In Part 3, we explore multi-valent targeting of G5 dendrimers in pursuit of further improving their specificity towards hepatic cancer cells.
Ultimately, this thesis provides insight into the utility of nanoparticle-based drug delivery systems not only for hepatic cancer therapy but for translational cancer therapeutics in general.