Chelating Complex Micelles (CCM) are a core-crosslinked polymeric micelle platform driven by metal coordination. Drugs are stably incorporated into the micelles via coordination bonds formed between the metal core and polymeric ligands. This platform enables extended half-life and optimized exposure in vivo, with controlled release achievable through chelators or corresponding metal ions.
Mechanism of Action
Lewis Acid/Base Design: The metal ion core acts as a Lewis acid; drugs and polymers bearing coordinating groups (e.g., PEG-b-PGA) function as Lewis bases. The three components spontaneously self-assemble into chelating complex micelles in aqueous solution. This encapsulation strategy does not require chemical modification of the drug.
Triggerable Release: In addition to passive diffusion, release can be modulated using specific chelators or homologous metal ions to accelerate or delay drug release. This enables externally controllable, triggered release.
Drug Delivery: Metal ion chelation enhances carrier stability. Lipophilicity and particle size of the micelles can be tuned to adjust drug half-life, reduce side effects, and increase drug specificity and biocompatibility.
Imaging, Diagnosis, and Therapy: When coordinated metal ions include Gd³⁺ (for MRI), ¹¹¹In (for SPECT), ⁹⁹ᵐTc (for SPECT), or ⁶⁸Ga (for PET), the micelles can simultaneously enable real-time imaging of drug biodistribution. This supports theranostics, the combination of therapy and diagnostics.
Differentiation from Traditional Micelles/Liposomes
Bond Stability: The micelle core is stabilized by coordination bonds, offering better resistance to dilution and protein corona effects compared to systems relying solely on hydrophobic interactions.
No Drug Modification Needed: Most drugs can be loaded through their inherent electron-donating groups (e.g., carboxylic acids, phosphates, imidazoles, thiols), eliminating the need for precursor synthesis or covalent derivatization.
Triggerable and Tunable Release: On-demand "on/off" or "fast/slow" drug release can be achieved using specific chelators or metal ions. This is especially beneficial for localized, high-exposure strategies in targeted therapies.
Validated Efficacy and Safety (Peer-Reviewed Journals)
Antibiotic Application (Colistin, CCM-CL):
In rats, intravenous 3 mg/kg: t₁/₂ ≈ 102 min (CCM-CL) vs. 12 min (free drug); AUC₀–∞ increased by ~4.95×
Expanded safety window: Acute toxicity NOAEL increased from 8 to 13 mg/kg. 14-day survival rate in severe infection mouse model: 80% (CCM-CL) vs. 30% (free drug). Reference: Antibiotics 2023; DOI: 10.3390/antibiotics12050836
Radioprotection Application (CCM-Ami): In whole-body irradiated mice, CCM-Ami (PEG-b-PGA × Amifostine) showed significant radioprotective effects when administered prior to radiation exposure. （Reference: Health Physics, 2015）
Clinical Development (United States)
RadProtect® (CCM-Ami): U.S. Phase 1 clinical trial in healthy volunteers for safety and pharmacokinetics. → ClinicalTrials.gov ID: NCT02587442
