Surface charge switchable fluorinated small molecular micelles for enhanced photodynamic therapy for bacterial infections.

Photodynamic therapy (PDT) employs reactive oxygen species (ROS) from a photosensitizer (PS) under light, inhibiting multi-drug resistance in bacteria. However, hypoxic conditions in infection sites and biofilms challenge PDT efficiency. We developed fluorinated small molecular micelles (PF-CBMs) as PS carriers to address this, relieving hypoxia and enhancing PS penetration into biofilms. Perfluorocarbons in PF-CBMs transport more oxygen due to their excellent oxygen-dissolving capability. Fluorination enhances loading capacity and serum stability, reduces premature release, and improves cellular uptake, to improve PDT efficacy. PF-CBMs, with acid-induced surface charge transformation, exhibit superior biofilm penetration, resulting in increased antibiofilm activity of PDT. Compared to fluorine-free micelles (PC-CBMs), PF-CBMs demonstrate better serum stability, higher drug loading, and reduced premature release, leading to significantly improved antibacterial efficacy in vitro and in vivo. In conclusion, fluorinated micelles with surface charge reversal enhance PDT for antibacterial and antibiofilm applications.

Lipase and pH-responsive diblock copolymers featuring fluorocarbon and carboxyl betaine for methicillin-resistant staphylococcus aureus infections.

The emergence of multidrug-resistant bacteria along with their resilient biofilms necessitates the development of creative antimicrobial remedies. We designed versatile fluorinated polymer micelles with surface-charge-switchable properties, demonstrating enhanced efficacy against Methicillin-Resistant Staphylococcus Aureus (MRSA) in planktonic and biofilm states. Polymethacrylate diblock copolymers with pendant fluorocarbon chains and carboxyl betaine groups were prepared using reversible addition-fragmentation chain transfer polymerization. Amphiphilic fluorinated copolymers self-assembled into micelles, encapsulating ciprofloxacin in their cores (CIP@FCBMs) for antibacterial and antibiofilm applications. As a control, fluorine-free copolymer micelles loaded with ciprofloxacin (CIP@BCBMs) were prepared. Although both CIP@FCBMs and CIP@BCBMs exhibited pH-responsive surface charges and lipase-triggered drug release, CIP@FCBMs exhibited powerful antimicrobial and antibiofilm activities in vitro and in vivo, attributed to superior serum stability, higher drug loading, enhanced fluorination-facilitated cellular uptake, and lipase-triggered drug release. Collectively, reversing surface charge, on-demand antibiotic release, and fluorination-mediated nanoparticles hold promise for treating bacterial infections and biofilms.

Counterion-induced antibiotic-based small-molecular micelles for methicillin-resistant Staphylococcus aureus infections.

A new counterion-induced small-molecule micelle (SM) with surface charge-switchable activities for methicillin-resistant Staphylococcus aureus (MRSA) infections is proposed. The amphiphilic molecule formed by zwitterionic compound and the antibiotic ciprofloxacin (CIP), via a "mild salifying reaction" of the amino and benzoic acid groups, can spontaneously assemble into counterion-induced SMs in water. Through vinyl groups designed on zwitterionic compound, the counterion-induced SMs could be readily cross-linked using mercapto-3, 6-dioxoheptane by click reaction, to create pH-sensitive cross-linked micelles (CSMs). Mercaptosuccinic acid was also decorated on the CSMs (DCSMs) by the same click reaction to afford charge-switchable activities, resulting in CSMs that were biocompatible with red blood cells and mammalian cells in normal tissues (pH 7.4), while having strong retention to negatively charged bacterial surfaces at infection sites, based on electrostatic interaction (pH 5.5). As a result, the DCSMs could penetrate deep into bacterial biofilms and then release drugs in response to the bacterial microenvironment, effectively killing the bacteria in the deeper biofilm. The new DCSMs have several advantages such as robust stability, a high drug loading content (∼ 30%), easy fabrication, and good structural control. Overall, the concept holds promise for the development of new products for clinical application. STATEMENT OF SIGNIFICANCE: We fabricated a new counterion-induced small-molecule micelle with surface charge-switchable activities (DCSMs) for methicillin-resistant Staphylococcus aureus (MRSA) infections. Compared with reported covalent systems, the DCSMs not only have improved stability, high drug loading content (∼ 30%), and good biosafety, but also have the environmental stimuli response, and antibacterial activity of the original drugs. As a result, the DCSMs exhibited enhanced antibacterial activities against MRSA both in vitro and in vivo. Overall, the concept holds promise for the development of new products for clinical application.

Antibiotic-based small molecular micelles combined with photodynamic therapy for bacterial infections.

The appearance of multidrug-resistant bacteria and the formation of bacterial biofilms have necessitated the development of alternative antimicrobial therapeutics. Antibiotics conjugated with or embedded in nano-drug carriers show a great potential and advantage over free drugs, but the mass proportion of carriers generally exceeds 90% of the nano-drug, resulting in low drug loading and limited therapeutic output. Herein, we fabricated a nanocarrier using antibiotics as the building blocks, minimizing the use of carrier materials, significantly increasing the drug loading content and treatment effect. Firstly, we conjugated betaine carboxylate with ciprofloxacin (CIP) through an ester bond to form the amphiphilic conjugate (CIP-CB), which self-assembled into micelles (CIP-CBMs) in aqueous solutions, with a CIP loading content as high as 65.4% and pH-induced surface charge reversal properties. Secondly, a model photosensitizer (5, 10, 15, 20-tetraphenylporphyrin (TPP)) was encapsulated in CIP-CBMs, generating infection-targeted photodynamic/antibiotic combined nanomedicines (denoted as TPP@CIP-CBMs). Upon accumulation at infection sites or in deep bacterial biofilms, the ester bond between the betaine carboxylate and CIP is cleaved to release free TPP and CIP, leading to a synergetic antibacterial and antibiofilm activity in vitro and in vivo.

Surface-Charge-Switchable and Size-Transformable Thermosensitive Nanocomposites for Chemo-Photothermal Eradication of Bacterial Biofilms in Vitro and in Vivo.

The appearance of multidrug-resistant bacteria and their biofilms presents a serious threat to modern medical systems. Herein, we fabricated a novel gold-nanorod-based chemo-photothermal-integrated antimicrobial platform with surface-charge-switchable and near-infrared (NIR)-induced size-transformable activities that show an enhanced killing efficiency against methicillin-resistant Staphylococcus aureus (MRSA) in both planktonic and biofilm phenotypes. The nanocomposites are prepared by in situ copolymerization using N-isopropyl acrylamide (NIPAM), acrylic acid (AA), and N-allylmethylamine (MAA) as monomers on the surfaces of gold nanorods (GNRs). Ciprofloxacin (CIP) is loaded onto polymer shells of nanocomposites with a loading content of 9.8%. The negatively charged nanocomposites switch to positive upon passive accumulation at the infectious sites, which promotes deep biofilm penetration and bacterial adhesion of the nanoparticles. Subsequently, NIR irradiation triggers the nanocomposites to rapidly shrink in volume, further increasing the depth of biofilm penetration. The NIR-triggered, ultrafast volume shrinkage causes an instant release of CIP on the bacterial surface, realizing the synergistic benefits of chemo-photothermal therapy. Both in vitro and in vivo evidence demonstrate that drug-loaded nanocomposites could eradicate clinical MRSA biofilms. Taken together, the multifunctional chemo-photothermal-integrated antimicrobial platform, as designed, is a promising antimicrobial agent against MRSA infections.