MAASTRICHT, The Netherlands—The number of companies fighting against cancer is matched only by the number of varied approaches being taken, and one player, privately held Cristal Therapeutics, is seeing big potential by thinking small. The company's CriPec platform is focused on the development of customized nanomedicines, and Cristal Therapeutics recently announced the publication of three articles detailing their exploration of this platform.
The CriPec platform, as noted on Cristal Therapeutics' website, “consists of tuneable polymers and biodegradable drug linkers that allow for the rational design and straightforward manufacturing of custom-made nanomedicines.” These nanomedicines are assembled in four steps: 1. derivatization of a drug molecule with a linker, 2. the CriPec polymer self-assembles with the drug-linker into polymeric micelles, 3. immediate crosslinking of both the CriPec polymer and the drug-linker results in transiently stable nanoparticles and 4. purification.
Cristal Therapeutics' nanomedicines offer prolonged circulation thanks to the polyethyleneglycol stealth layer that comprises the surface of the particle. This layer “prevents rapid elimination of the nanoparticles from the bloodstream,” thereby offering “higher accumulation at the diseased tissue,” the company website explains. Customized drug release is another benefit, as the linkers that entrap the drug in the CriPec polymer determines the site and rate at which the drug is released. A variety of drugs, including hydrophilic and -phobic small molecules and even large peptides can be combined with these CriPec polymers.
Dr. Cristianne Rijcken, founder and chief scientific officer of Cristal Therapeutics, co-authored the three pieces, which appeared in Nano Today, Journal of Controlled Release and Biomaterials.
In the Nano Today article, titled “Core-crosslinked polymeric micelles: Principles, preparation, biomedical applications and clinical translation,” the authors “summarize recent advances in the CCPM [core-crosslinked polymeric micelles] field, addressing the chemistry involved in preparing them, their in-vitro and in-vivo performance, potential biomedical applications and guidelines for efficient clinical translation.”
Polymeric micelles are widely used to help deliver hydrophobic drugs, and recent evidence suggests that micelles need to be stabilized for efficient drug targeting in order to prevent premature disintegration. Core-crosslinking, the paper notes, “is among the most popular methods to improve the in vivo stability of PM, and a number of core-crosslinked polymeric micelles have demonstrated promising efficacy in animal models. The latter is particularly true for CCPM in which (pro-) drugs are covalently entrapped. This ensures proper drug retention in the micelles during systemic circulation, efficient drug delivery to pathological sites via EPR, and tailorable drug release kinetics at the target site.”
The second paper, appearing in Biomaterials, was titled “Complete regression of breast tumour with a single dose of docetaxel-entrapped core-cross-linked polymeric micelles.” After dosing tumor-bearing mice with a single dose of docetaxel-entrapped core-cross-linked polymeric micelles (CriPec docetaxel, Cristal Therapeutics' lead candidate), the mice saw complete regression of breast tumors. CriPec docetaxel accumulated in tumor tissue at least 20 times more than an equivalent dose of Taxotere, the commercially available docetaxel. The authors noted in the abstract that a single intravenous dose “enabled complete regression of both small (∼150 mm3) and established (∼550 mm3) tumours, leading to 100-percent survival of the animals.” CriPec docetaxel also showed superior tolerability compared to Taxotere.
The third publication, “A novel approach for the intravenous delivery of leuprolide using core-cross-linked polymeric micelles,” was published in Journal of Controlled Release. The authors sought to combat the issue of rapid renal elimination of drugs by linking leuprolide, a model hormone peptide, to “core-cross-linked polymeric micelles (CCL-PMs) via two different hydrolysable ester linkages, thereby yielding a nanoparticulate system with tuneable drug release kinetics. The ester linkage that provided the slowest peptide release kinetics was selected for in-vivo evaluation,” the abstract explains. As a result, these nanomedicines “showed a prolonged circulation half-life (14.4 h) following a single intravenous injection in healthy rats, and the released leuprolide was detected in blood for 3 days.”
“These findings clearly demonstrate the added value of the CriPec platform, being the improved therapeutic index in oncology for various drug molecules. Relative to the worldwide developments in nanomedicine, the CriPec platform is really state-of-the-art and capable of translating the biological requirements into a fully tuneable nanomedicine with superior therapeutic outcome,” says Prof. Twan Lammers, head of the department of nanomedicine and theranostics at RWTH Aachen University Clinic in Germany.