UC Davis

Over the past two decades, polymeric micelles have been investigated as carriers to provide increased solubility and improved in vivo circulation for anticancer drugs with poor distribution, such as paclitaxel (PTX) and doxorubicin. Furthermore, micelles approximately 10–100nm take advantage of the enhanced permeability and retention (EPR) effect for preferential localization to tumors. However, these micelles are thermo-dynamic systems constantly dissociating and associating into their monomers, thereby posing a challenge whereby these micelles fall below critical micelle concentration (CMC). To address this, hafnium (Hf), demonstrated as a radio-enhancer in metal- organic frameworks (MOFs), was utilized to cross-link linear-dendritic amphiphilic polymers (telodendrimers) to develop a self-assembling polymeric nanoparticle (NP) with enhanced stability. The dendrimer portion was synthesized via solution-phase condensation reactions beginning with MeO-PEG5000-NH2 utilizing stepwise peptide chemistry of branched lysine residues. The resulting amphiphilic dendrimer contained 8 terminal amines which were then coupled with 4 cholic acid (CA) moieties and 4 carboxylic acid (COOH) functional groups to yield a PEG5000-CA4/COOH4 telodendrimer. The resulting hybrid telodendrimers self-assembled into ~30 nm nanoparticles, as measured by dynamic light scattering (DLS), and upon addition of HfCl4, cross-linking chelation occurred to stabilize the nanoparticles up to 20 mg/mL of sodium dodecyl sulfate (SDS). Furthermore, this Hf-NP shows efficient drug loading and uptake by a number of cancer cell lines, as observed under confocal microscopy. Development of this novel hafnium cross-linked drug-delivery nanoparticle not only boasts increased in vivo stability during circulation, but also serves as a potent radio-enhancer for more efficacious radiotherapy.