Pharmaceutical Applications Of Metal-chelating Polymeric Micelles

Treatment of iron overload diseases usually involves the removal of excess iron from body with iron chelators.These small molecular iron chelators require a consecutive administration due to their short half-life,leading to poor patient compliance.To prolong the half-life of iron chelators and reduce their toxic sideeffects,a model chelator,deferiprone(DFP)was covalently linked to amphiphilic poly(ethylene glycol)-polypeptide block copolymer(m PEG-P(Glu))that could assemble into micelles.The free DFP generally coordinates with iron in a ratiometric manner(3:1).Surprisingly,It was found that the DFP-conjugated polymeric micelles(m PEG-P(Glu-DFP))enhanced the iron chelating efficiency.We presumed that the assembly-induced DFP packing in the micellar cores could restrict its conformational freedom.Hence DFP/iron coordination ratio in micelles was reduced(< 3:1),which led to an enhanced chelation performance of DFP.Our hypothesis was demonstrated by comparing the difference of iron chelating efficiency before and after micelle formation.It was shown that when the polymer concentration was lower than the critical micelle concentration(CMC),the polymer exhibited similar iron chelating efficiency to free DFP,while the iron chelating efficiency was enhanced when the polymer assemblied into micelles.The stability of m PEG-P(Glu-DFP)micelle was assessed by determining its CMC,kinetic change of micelle size in phosphate buffered saline(PBS),and the kinetic fluorescence intensity of Rhodamine B(Rh B)-labbled micelles in fetal bovine serum(FBS).The micellar nanocarrier exhibited good stability,which could extend the systemic circulation in contrast to the free DFP.The part of my work opened new avenues for developing novel nanomedicines for iron overload diseases.The second part of this thesis involves iron-triggered cisplatin delivery using polymeric chelating micelles.Currently,amphilic brush polymers containing carboxyl side-chain was used to bind cisplatin via the COOH-Pt bond and form colloidal micelles.It has been one of the most popular methods to extend the half-life of cisplatin and reduce its side-effects.However,the COOH-Pt bond is not stable,resulting in premature cisplatin release and poor delivery efficiency.To address this,we employed DFP polymers to load cisplatin via the coordination bond that shows higher stability,producing cisplatin-bearing polymeric micelles.Upon endocytosis of micelles,the intracelluar iron could compete with DFP moiety to release cisplatin because of the extremely high DFP/iron binding affinity in contrast to that of DFP/cisplatin.In vitro spectroscopic analysis and cell viability assay proved this hypothesis.This part of work developed a novel micellar approach for iron-triggered delivery of cisplatin.