Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Secondary Amine Pendant ß-Peptide Polymers Displaying Potent Antibacterial Activity and Promising Therapeutic Potential in Treating MRSA-Induced Wound Infections and Keratitis.

Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking ß-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial ß-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.

Hidden complexity in membrane permeabilization behavior of antimicrobial polycations.

A promising alternative to classical antibiotics are antimicrobial peptides and their synthetic mimics (smAMPs) that supposedly act directly on membranes. For a more successful design of smAMPs, we need to know how the type of interaction with the membrane determines the type of membrane perturbation. How this, in turn, transfers into selectivity and microbial killing activity is largely unknown. Here, we characterize the action of two smAMPs: MM:CO (a copolymer of hydrophobic cyclooctyl subunits and charged ß-monomethyl-α-aminomethyl subunits) and the highly charged poly-NM (a homopolymer of α-aminomethyl subunits). By thorough characterization of vesicle leakage experiments, we elucidate complex membrane perturbation behavior in zwitterionic or negatively charged vesicles. Vesicle leakage data does not entirely agree with the growth inhibition of microbes. Our ensemble of advanced membrane permeabilization approaches clarifies these discrepancies. Long cumulative leakage kinetics show that the two smAMPs act either by transient leakage or by rare stochastic leakage events that occur at charge neutralization in the sample. We determine the strengths of individual leakage events induced by the smAMPs in membranes of various compositions. These strengths indicate changes in leakage mechanism over time and concentration range. Thus, our sophisticated analysis of vesicle leakage experiments reveals a fine-tuned flexibility in membrane permeabilization mechanisms. These details are indispensable in judging and designing membrane-active compounds.

Microbial Metabolite Inspired ß-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of ß-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL-1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.

Using In Vivo Assessment on Host Defense Peptide Mimicking Polymer-Modified Surfaces for Combating Implant Infections.

Infections have accounted for the majority of failures in implants over the past decades. Host defense peptide mimicking polymers have been considered as one of the promising antimicrobial candidates for their cost-effective synthesis, broad-spectrum antimicrobial activity, low propensity to induce drug resistance, and remarkable biocompatibility. In this review, covalent-grafting strategies are mainly discussed to tether host defense peptide mimicking polymers on surfaces, aiming to obtain potent antimicrobial activity. In addition to the antimicrobial function, we review the antimicrobial mechanism of these polymer-modified antimicrobial surfaces in precedent literatures. We also review the in vivo subcutaneous implant infection models that are critical assessments for potential biomedical applications. In the end, we provide our perspective on the future development of this field, especially for biomedical applications.

Practical Preparation of Infection-Resistant Biomedical Surfaces from Antimicrobial ß-Peptide Polymers.

Tackling microbial infection associated with biomaterial surfaces has been an urgent need. Synthetic ß-peptide polymers can mimic host defense peptides and have potent antimicrobial activities without driving the bacteria to develop antimicrobial resistance. Herein, we demonstrate a plasma surface activation-based practical ß-peptide polymer modification to prepare antimicrobial surfaces for biomedical materials such as thermoplastic polyurethane (TPU), polytetrafluoroethylene, polyvinyl pyrrolidone, polyvinyl chloride, and polydimethylsiloxane. The ß-peptide polymer-modified surfaces demonstrated effective killing on drug-resistant Gram-positive and Gram-negative bacteria. The antibacterial function retained completely even after the ß-peptide polymer-modified surfaces were stored at ambient temperature for at least 2 months. Moreover, the optimum ß-peptide polymer (50:50 DM-Hex)-modified surfaces displayed no hemolysis and cytotoxicity. In vivo study using methicillin-resistant Staphylococcus aureus (MRSA)-pre-incubated TPU-50:50 DM-Hex surfaces for subcutaneous implantation revealed a 3.4-log reduction of MRSA cells after the implantation for 11 days at the surrounding tissue of implanted TPU sheet and significant suppression of infection, compared to bare TPU control. These results imply promising and practical applications of ß-peptide polymer tethering to prepare infection-resistant surfaces for biomedical materials and devices.