Formulation Development Forum: Boronate Cross-linked Micelles - Pharmaceutical Technology

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Formulation Development Forum: Boronate Cross-linked Micelles
A new class of nanoparticles hold promise for preventing premature drug release and offering greater accuracy and effectiveness in drug delivery.

Pharmaceutical Technology
Volume 36, Issue 2, pp. 44

A new class of nanoparticles, synthesized by a research team at the University of California, Davis, to prevent premature drug release, holds promise for greater accuracy and effectiveness in delivering cancer drugs to tumors. Kit Lam, professor and chair of the Department of Biochemistry and Molecular Medicine and his team reported 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.

The researchers reported that micelles reversibly cross-linked by boronate esters show in vitro and in vivo stability and thus minimize premature drug release under physiological conditions. After reaching the tumor sites, drug release is activated by cleavage of the boronate esters by the acidic conditions around the tumor or in the target cells or by the administration of mannitol (1). A micelle is an aggregate of surfactant molecules dispersed in water-based liquid such as saline. They are nanosized, about 25–50 nm , and can function as nanocarriers for drug delivery. "This use of reversibly cross-linked targeting micellar nanocarriers to deliver anticancer drugs helps prevent premature drug release during circulation and ensures delivery of high concentrations of drugs to the tumor site," said Yuanpei Li, a postdoctoral fellow in Lam's laboratory who created the novel nanoparticle with Lam, in a Jan. 18, 2012, University of California at Davis press release. "It holds great promise for a significant improvement in cancer therapy."

Stimuli-responsive nanoparticles are gaining attention in the field of drug delivery due to their ability to transform in response to specific triggers, notes the university release. Among these nanoparticles, stimuli-responsive cross-linked micelles (SCMs) can serve as a nanocarrier system for tumor-targeting drug delivery.

SCMs and other nanoparticle systems seek to address the problem of premature drug release, which results in a drug not delivering its payload to a given 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, according to the release.

The dual-responsive boronate cross-linked micelles that Lam's team has developed are a second generation of SCMs able to respond to multiple stimuli as tools for accomplishing the multistage delivery of drugs to a complex in vivo tumor micro-environment, according to the university release. 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 research team has optimized the stability of the resulting boronate cross-linked micelles as well as their stimuli-response to acidic pH and mannitol.

This nanocarrier platform shows 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.


1. K. Lam et al., "Well Defined, Reversible Boronate Crosslinked Nanocarriers for Targeted Drug Delivery in Response to Acidic pH Values and cis-Diols," Angew. Chem., Int. Ed. Engl. online, DOI:10.1002/anie.201107144, Jan. 17, 2012.


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