UC Davis researchers refine nanoparticles for more accurate delivery of cancer drugs
A new class of nanoparticles, synthesized by a UC Davis research team to prevent premature drug release, holds promise for greater accuracy and effectiveness in delivering cancer drugs to tumors. The work is published in the current issue of Angewandte Chemie, a leading international chemistry journal.
In their paper, featured on the inside back cover of the journal, Kit Lam, professor and chair of the Department of Biochemistry and Molecular Medicine, and his team report on the synthesis of a novel class of micelles called dual-responsive boronate cross-linked micelles (BCMs) , which produce physicochemical changes in response to specific triggers.
A micelle is an aggregate of surfactant molecules dispersed in water-based liquid such as saline. Micelles are nano-sized, measuring about 25-50 nanometers (one nanometer is one billionth of a meter), and can function as nanocarriers for drug delivery.
BCMs are a unique type of micelle, which releases the payload quickly when triggered by the acidic micro-environment of the tumor or when exposed to an intravenously administered chemical compound such as mannitol, an FDA-approved sugar compound often used as a diuretic agent, which interferes with the cross-linked micelles.
"This use of reversibly cross-linked targeting micellar nanocarriers to deliver anti-cancer drugs helps prevent premature drug release during circulation and ensures delivery of high concentrations of drugs to the tumor site," said first author Yuanpei Li, a postdoctoral fellow in Lam's laboratory who created the novel nanoparticle with Lam. "It holds great promise for a significant improvement in cancer therapy."
Stimuli-responsive nanoparticles are gaining considerable attention in the field of drug delivery due to their ability to transform in response to specific triggers. Among these nanoparticles, stimuli-responsive cross-linked micelles (SCMs) represent a versatile nanocarrier system for tumor-targeting drug delivery.
Too often, nanoparticles release drugs prematurely and miss their target. SCMs can better retain the encapsulated drug and minimize its premature release while circulating in the blood pool. The introduction of environmentally sensitive cross-linkers makes these micelles responsive to the local environment of the tumor. In these instances, the payload drug is released primarily in the cancerous tissue.
The dual-responsive boronate cross-linked micelles that Lam's team has developed represent an even smarter second generation of SCMs able to respond to multiple stimuli as tools for accomplishing the multi-stage delivery of drugs to the complex in vivo tumor micro-environment. These BCMs deliver drugs based on the self-assembly of boronic acid-containing polymers and catechol-containing polymers, both of which make these micelles unusually sensitive to changes in the pH of the environment. The team has optimized the stability of the resulting boronate cross-linked micelles as well as their stimuli-response to acidic pH and mannitol.
This novel nano-carrier platform shows great promise for drug delivery that minimizes premature drug release and can release the drug on demand within the acidic tumor micro-environment or in the acidic cellular compartments when taken in by the target tumor cells. It also can be induced to release the drug through the intravenous administration of mannitol.
The study was funded by grants from the National Institutes of Health and a Department of Defense Breast Cancer Research Program Postdoctoral Award. Other authors are Wenwu Xiao, Kai Xiao, Lorenzo Berti, Harry P. Tseng, and Gabriel Fung of UC Davis; and Juntao Luo of SUNY Upstate Medical University, Syracuse, New York.