UC Davis

Smart nanoparticles differ from conventional nanoparticles due to their capability of reacting or being directed to biological signals for precise targeted drug delivery to the tumor microenvironment1 and therefore are emerging as a highly promising platform for precise cancer treatment. With the rapid progression of multi-drug resistance and metastasis, smart nanoparticles offer rapid advancements in different treatment modalities for oncology. An ideal smart nanoparticle should meet several basic criteria, such as stimulus responsive material or structure, stable nanometer size, adjustable surface charge, high encapsulation capacity, biocompatibility, degradability, and low toxicity, etc.1 Equipped with tumor targeting ligand and stimulus responsive elements, these smart nanoparticles can preferentially accumulate in the tumor microenvironment and release the chemotherapeutic agents. Moreover, their capacity for co-delivering both therapeutics and diagnostic agents can significantly propel the advancement of personalized medicine.

This thesis focuses on two different platforms of smart nanoparticle therapy coupled with immunotherapy, illustrated by two different projects and each is explained in one chapter. Chapter 1 discusses a self-assembling micelle designed to deliver an immunomodulator and a photosensitizer, while being decorated with PLZ4, a bladder cancer- targeting ligand. This ligand selectively targets ανβ3 integrin over-expressed on surface of bladder cancer cell lines as well as all five primary bladder cancer cells sourced from human patients, exhibiting no affinity for normal urothelial cells. Chapter 2 explores a different drug-delivery platform that utilizes the endogenous protein, human albumin serum (HSA). This vehicle is site-specifically modified with two targeting ligands: LBF127, which locates surface receptors present in triple-negative breast cancer cells, and LLP2A, which attaches to α4β1 integrin on activated NK cells and T-cells. This modification results in an amplified synergistic anti-tumor effect overall through the targeted delivery and accumulation of bortezomib, a potent proteosome inhibitor currently used in the clinic.