Bacterial infections are mostly due to bacteria in their biofilm mode-ofgrowth, making them recalcitrant to antibiotic penetration. In addition, the number of bacterial strains intrinsically resistant to available antibiotics is alarmingly growing. This study reports that micellar nanocarriers with a poly(ethylene glycol) shell fully penetrate staphylococcal biofilms due to their biological invisibility. However, when the shell is complemented with poly(β-amino ester), these mixed-shell micelles become positively charged in the low pH environment of a biofilm, allowing not only their penetration but also their accumulation in biofilms without being washed out, as do single-shell micelles lacking the pH-adaptive feature. Accordingly, bacterial killing of multidrug resistant staphylococcal biofilms exposed to proto porphyrin IX-loaded mixed-shell micelles and after light-activation is superior compared with single-shell micelles. Subcutaneous infections in mice, induced with vancomycin-resistant, bioluminescent staphylococci can be eradicated by daily injection of photoactivatable protoporphyrin IX-loaded, mixed-shell micelles in the bloodstream and light-activation at the infected site. Micelles, which are not degraded by bacterial enzymes in the biofilm, are degraded in the liver and spleen and cleared from the body through the kidneys. Thus, adaptive micellar nanocarriers loaded with lightactivatable antimicrobials constitute a much-needed alternative to current antibiotic therapies.

Because of the mounting prevalence of complicated infections induced by multidrug-resistant bacteria, it is imperative to develop innovative and efficient antibacterial agents. In this work, we design a novel polymeric micelle for simultaneous decorating of silver nanoparticles and encapsulating of curcumin as a combination strategy to improve the antibacterial efficiency. In the constructed combination system, silver nanoparticles were decorated in the micellar shell because of the in situ reduction of silver ions, which were absorbed by the poly(aspartic acid) (PAsp) chains in the shell. Meanwhile, natural curcumin was encapsulated into the poly(ε-caprolactone) (PCL) core of the micelle through hydrophobic interaction. This strategy could prevent aggregation of silver nanoparticles and improve the water solubility of curcumin at the same time, which showed enhanced antibacterial activity toward Gram-negative P.aeruginosa and Gram-positive S.aureus compared with sliver-decorated micelle and curcumin-loaded micelle alone, due to the cooperative antibacterial effects of the silver nanoparticles and curcumin. Furthermore, the achieved combinational micelles had good biocompatibility and low hemolytic activity. Thus, our study provides a new pathway in the rational design of combination strategy for efficiently preventing the ubiquitous bacterial infections.

No abstract

The miserable targeting performance of nanocarriers for cancer therapy arises largely from the rapid clearance from blood circulation and the major accumulation in the organs of the reticuloendothelial system (RES), leading to inefficient enhanced permeability and retention (EPR) effect after intravenous injection (i.v.). Herein, we reported an efficient method to prolong the blood circulation of nanoparticles and decrease their deposition in liver and spleen. In this work, we fabricated a series of mixed shell micelles (MSMs) with approximately the same size, charge and core composition but with varied hydrophilic/hydrophobic ratios in the shell through spontaneously self-assembly of block copolymers poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLys) and poly(N-isopropylacrylamide)-block-poly(aspartic acid) (PNIPAM-b-PAsp) in aqueous medium. The effect of the surface heterogeneity on the in vivo biodistribution was systematically investigated through in vivo tracking of the (125)I-labeled MSMs determined by Gamma counter. Compared with single PEGylated micelles, some MSMs were proved to be significantly efficient with more than 3 times lower accumulation in liver and spleen and about 6 times higher concentration in blood at 1 h after i.v.. The results provide us a novel strategy for future development of long-circulating nanocarriers for efficient cancer therapy.