RESUMEN
Polymeric micelles are among the most extensively used drug delivery systems. Key properties of micelles, such as size, size distribution, drug loading, and drug release kinetics, are crucial for proper therapeutic performance. Whether polymers from more controlled polymerization methods produce micelles with more favorable properties remains elusive. To address this question, we synthesized methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers of three different comparable molecular weights (â¼9, 13, and 20 kDa), via both conventional free radical (FR) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers were subsequently employed to prepare empty and paclitaxel-loaded micelles. While FR polymers had relatively high dispersities (D â¼ 1.5-1.7) compared to their RAFT counterparts (D â¼ 1.1-1.3), they formed micelles with similar pharmaceutical properties (e.g., size, size distribution, critical micelle concentration, cytotoxicity, and drug loading and retention). Our findings suggest that pharmaceutical properties of mPEG-b-p(HPMAm-Bz) micelles do not depend on the synthesis route of their constituent polymers.
Asunto(s)
Electrones , Micelas , Polimerizacion , Polietilenglicoles , Polímeros , Portadores de FármacosRESUMEN
Nanomedicine holds promise for potentiating drug combination therapies. Increasing (pre)clinical evidence is available exemplifying the value of co-formulating and co-delivering different drugs in modular nanocarriers. Taxanes like paclitaxel (PTX) are widely used anticancer agents, and commonly combined with corticosteroids like dexamethasone (DEX), which besides for suppressing inflammation and infusion reactions, are increasingly explored for modulating the tumor microenvironment towards enhanced nano-chemotherapy delivery and efficacy. We here set out to develop a size- and release rate-tunable polymeric micelle platform for co-delivery of taxanes and corticosteroids. We synthesized amphiphilic mPEG-b-p(HPMAm-Bz) block copolymers of various molecular weights and used them to prepare PTX and DEX single- and double-loaded micelles of different sizes. Both drugs could be efficiently co-encapsulated, and systematic comparison between single- and co-loaded formulations demonstrated comparable physicochemical properties, encapsulation efficiencies, and release profiles. Larger micelles showed slower drug release, and DEX release was always faster than PTX. The versatility of the platform was exemplified by co-encapsulating two additional taxane-corticosteroid combinations, demonstrating that drug hydrophobicity and molecular weight are key properties that strongly contribute to drug retention in micelles. Altogether, our work shows that mPEG-b-p(HPMAm-Bz) polymeric micelles serve as a tunable and versatile nanoparticle platform for controlled co-delivery of taxanes and corticosteroids, thereby paving the way for using these micelles as a modular carrier for multidrug nanomedicine.
RESUMEN
AIMS: Sepsis is a potentially fatal illness that can lead to impairment of multiple organs such as liver. The condition is deeply associated with oxidative stress and inflammation. Monomethyl fumarate (MMF) has manifested antioxidant and immunomodulatory properties. The aim of current study was to evaluate protective effects of MMF in sepsis-induced hepatic dysfunction. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). Wistar rats were assigned to one of sham, CLP, CLPâ¯+â¯dexamethasone (as positive control of inflammation) and CLPâ¯+â¯MMF groups. Levels of serum IL-1ß, IL-6, IL-10, AST, ALT and γGT were quantified. Furthermore, Hepatic levels of GSH and MDA and mRNA expression of TNF and NFKBIA along with hepatic protein level of TLR-4 were assessed. Also, histopathological study of liver was carried out to evaluate hepatic injuries. KEY FINDINGS: Septic rats demonstrated risen levels of IL-1ß, IL-6, IL-10, AST, ALT and γGT, while treatment with dexamethasone or MMF attenuated these levels. Moreover, enhancements in protein level of TLR-4 and mRNA levels of TNF and NFKBIA were observed in CLP rats. These elevations were mitigated in CLP-induced rats that were treated with either dexamethasone or MMF. Treatment with dexamethasone or MMF also shifted sepsis-induced disturbance in the levels of GSH and MDA towards sham levels. Hepato-protective effects of dexamethasone and MMF were further confirmed by histopathological observations. SIGNIFICANCE: Our findings imply that MMF alleviates sepsis-induced hepatic dysfunction by mitigating the inflammatory and oxidative state and this effect is at least partly mediated by the inhibition of TLR-4/NF-κB signalling pathway.