Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles

Cristianne J.F. Rijcken*, Federica De Lorenzi, Ilaria Biancacci, Rob G.J.M. Hanssen, Marielle Thewissen, Qizhi Hu, Florence Atrafi, Rob M.J. Liskamp, Ron H.J. Mathijssen, Iris H.C. Miedema, C. Willemien Menke - van der Houven van Oordt, Guus A.M.S. van Dongen, Danielle J. Vugts, Matt Timmers, Wim E. Hennink, Twan Lammers

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

Nanomedicines are used to improve the efficacy and safety of pharmacotherapeutic interventions. Unraveling the biological behavior of nanomedicines, including their biodistribution and target site accumulation, is essential to establish design criteria that contribute to superior performance. CriPec® technology is based on amphiphilic methoxy-poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide lactate] (mPEG-b-pHPMAmLacn) block copolymers, which are designed to upon self-assembly covalently entrap active pharmaceutical ingredients (API) in core-crosslinked polymeric micelles (CCPM). Key features of CCPM are a prolonged circulation time, high concentrations at pathological sites, and low levels of accumulation in the majority of healthy tissues. Proprietary hydrolysable linkers allow for tunable and sustained release of entrapped API, including hydrophobic and hydrophilic small molecules, as well as peptides and oligonucleotides. Preclinical imaging experiments provided valuable information on their tumor and tissue accumulation and distribution, as well as on uptake by cancer, healthy and immune cells. The frontrunner formulation CPC634, which refers to 65 nm-sized CCPM entrapping the chemotherapeutic drug docetaxel, showed excellent pharmacokinetic properties, safety, tumor accumulation and antitumor efficacy in multiple animal models. In the clinic, CPC634 also demonstrated favorable pharmacokinetics, good tolerability, signs of efficacy, and enhanced localization in tumor tissue as compared to conventional docetaxel. PET imaging of radiolabeled CPC634 showed quantifiable accumulation in ∼50 % of tumors and metastases in advanced-stage cancer patients, and demonstrated potential for use in a theranostic setting even when applied at a companion diagnostic dose. Altogether, the preclinical and clinical results obtained to date demonstrate that mPEG-b-pHPMAmLacn CCPM based on CriPec® technology are a potent, tunable, broadly applicable and well-tolerable platform for targeted drug delivery and improved anticancer therapy.

Original languageEnglish
Article number114613
JournalAdvanced Drug Delivery Reviews
Volume191
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Acknowledgements
CJFR, RH, MTh, QH and MTi are employees of Cristal Therapeutics. The other authors have no competing interest to disclose. The authors gratefully acknowledge financial support by the European Research Council (TL – ERC Consolidator Grant 864121: Meta-Targeting), the European Fund for Regional Development (FDL, TL – TAKTIRA: Project number: EFRE-0801767)), the German Research Foundation (IB, TL – DFG: GRK2375 (Project number: 331065168) and SFB1066), Horizon SME grant (784127), and the German Federal Ministry of Research and Education (TL; BMBF: Gezielter Wirkstofftransport, PP-TNBC, Project number 16GW0319K).

Publisher Copyright: © 2022 Elsevier B.V.

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