Synthesis, characterization, and tumor targeting of novel pH sensitive nanoparticles
Many contemporary therapeutic and imaging approaches to cancer treatment are based on specific tumor-targeting biomarkers such as antibody or vitamin binding. Although there are significant successes, the inter- and intra-heterogeneity of tumors, their complexity, and their ability to adapt to new conditions often create parts of a tumor that do not express enough of the biomarker to be targeted. On the other hand, extracellular tumor acidity, resulting from the metabolic alterations of cancer cells, attracts a lot of attention as a novel general tumor biomarker. pH (Low) Insertion Peptides (pHLIP® peptides), discovered in our laboratory, represent a novel class of pH-responsive tumor-targeting delivery agents. ^ The main goal of this work was the development of novel pHLIP® peptide coated nanomaterials for cancer therapy. More specifically, we introduced and investigated: - a family of pHLIP® peptides (along with K-pHLIP, the pH-insensitive counterpart to pHLIP®); - fusogenic, PEGylated liposomes coated with pHLIP® peptide for the delivery of therapeutic molecules; - specific delivery to tumors of nanogold® clusters conjugated to the pHLIP® peptide; - novel pHLIP® and PEG coated spherical and spiked gold nanoparticles ^ A variety of rationally designed pHLIP® variants were characterized. It was shown how tuning the biophysical properties of the peptide–lipid bilayer interactions alter: i) tumor-targeting, ii) distribution in organs, and iii) blood clearance. Also presented, is the current understanding of the main principles of pHLIP® design. All pHLIP® coated nanomaterials in this work that have been administered to cancerous cells have shown a pH-dependent interaction in vitro and/or in vivo. ^ A novel type of pH-sensitive, “fusogenic” pHLIP® liposomes was developed. These pHLIP® liposomes displayed enhanced membrane fusion in a pH-dependent fashion that leads to the increase of cellular uptake and payload release in vitro, highlighting their future use as drug delivery agents. ^ The uptake and retention of nanogold® clusters in acidic tumors was significantly enhanced by conjugating the clusters with pHLIP® peptides, further supporting the significance of pHLIP® peptide’s presence in nanomaterial coating for tumor-targeting. Furthermore, K-pHLIP (the pH-insensitive version of pHLIP®) failed to target tumors in vivo. ^ A novel approach for the synthesis of pHLIP® and PEG coated spherical gold nanoparticles was introduced. These nanoparticles showed enhanced stability in solution and homogeneous tumor uptake with no staining of the surrounding muscle tissue. Potentially, they could be used for the enhancement of x-ray radiation. Novel spiked gold nanoparticles coated with pHLIP® and PEG were also created. Spiked particles exhibited plasmonic resonance in the near infrared region. The particle solutions were heated by an 805 nm laser, thereby demonstrating a potential application in photothermal therapy. We believe that pHLIP® coated nanomaterials will find a great range of applications in the treatment of cancerous tumors. (Abstract shortened by ProQuest.)^
Condensed matter physics|Nanotechnology|Biophysics
Jennifer L Daniels,
"Synthesis, characterization, and tumor targeting of novel pH sensitive nanoparticles"
Dissertations and Master's Theses (Campus Access).