•PZ-M prepared by mPEG-PLLA significantly increase water solubility of pyrinezolid.•PZ-M possess prolonged blood circulation time and increased oral bioavailability.•PZ-M has the potential to serve as a novel agent for MRSA-related pneumonia.Antibiotic-resistance by bacteria is a growing global concern within the healthcare field, and it has provided an impetus for continued antimicrobial development. Pyrinezolid (PZ), a novel oxazolidinone compound, can effectively inhibit most gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Though PZ is a promising antimicrobial candidate, the druggability of PZ is limited by its poor water solubility. Therefore, the amphipathic mPEG-PLLA copolymer was used to prepare the pyrinezolid micelles (PZ-M). Herein, we described the preparation, pharmacokinetic properties, tissue distribution, efficacy and toxicity of PZ-M. In vivo studies show that PZ-M possess prolonged blood circulation time and increased oral bioavailability compared with free PZ. Meanwhile, PZ-M increase lung PZ exposure and reduce liver and kidney exposure, which indicates that PZ-M may enhance the efficacy in vivo in MRSA-related pneumonia patients and decrease potential renal and hepatic toxicities.Preparation of PZ-M. (A) Chemical structure of pyrinezolid; (B) Schematic diagram of the preparation of PZ-M.Download high-res image (77KB)Download full-size image

Wound healing, a complex process involving several important biomolecules and pathways, requires efficient dressings to enhance the therapy effects. Electrospinning nanofiber mats for wound healing have attracted significant interest because of their unique properties including ultrathin diameters, high volume ratios, and three-dimensional structure that mimics the extracellular matrix. In this study, we synthesized grafted chitosans with improved solubility, resulting in circumventing the use of acidic solvents, such as acetic acid and trifluoroacetic acid, simplified the electrospinning processes and fabricated poly(vinyl alcohol)-free nanofibers. The model drug curcumin was encapsulated in the nanofibers, consisting of grafted chitosan and poly(propylene carbonate), by electrospinning, which gradually released the drug from the matrix in 288 hours. Moreover, the curcumin-loaded composite nanofibers showed excellent free-radical scavenging capabilities. The enhanced wound healing efficacy was confirmed by an in vivo test and approximately 100% wound closure ratio was observed in the 10% curcumin-loaded PPC/g-CS nanofibers group at day 21 post surgery, which was subsequently evidenced by haematoxylin and eosin stain and Masson's trichrome stain. Higher granulation scores and higher collagen contents were observed in the PPC/g-CS 10% curcumin group, showing significant differences among all the groups. These results demonstrated that the combination of grafted chitosan and curcumin improved the wound healing process. Moreover, electrospinning nanofibers based on the grafted polymer and curcumin showed potential for wound repair applications.

E-cadherin/catenin complex is crucial for cancer cell migration and invasion. The histidine-alanine-valine (HAV) sequence has been shown to inhibit a variety of cadherin-based functions. In this study, by fusing HAV and the classical tumor-targeting Arg-Gly-Asp (RGD) motif and Asn-Gly-Arg (NGR) motif to the apoptosis-inducing peptide sequence-AVPIAQK, a bifunctional peptide has been constructed with enhanced tumor targeting and apoptosis effects. This peptide is further processed as a nanoscale vector to encapsulate the hydrophobic drug docetaxel (DOC). Bioimaging analysis shows that peptide nanoparticles can penetrate into xenograft tumor cells with a significantly long retention in tumors and high tumor targeting specificity. In vivo, DOC/peptide NPs are substantially more effective at inhibiting tumor growth and prolonging survival compared with DOC control. Together, the findings of this study suggest that DOC/peptide NPs may have promising applications in pulmonary carcinoma therapy.

BRAF-V600E (1799T > A) is one of the most frequently reported driver mutations in multiple types of cancers, and patients with such mutations could benefit from selectively inactivating the mutant allele. Near this mutation site, there are two TTTN and one NGG protospacer-adjacent motifs (PAMs) for Cpf1 and Cas9 CRISPR nucleases, respectively. The 1799T > A substitution also leads to the occurrence of a novel NGNG PAM for the EQR variant of Cas9. We examined the editing efficacy and selectivity of Cpf1, Cas9, and EQR variant to this mutation site. Only Cpf1 demonstrated robust activity to induce specific disruption of only mutant BRAF, not wild-type sequence. Cas9 recognized and cut both normal and mutant alleles, and no obvious gene editing events were observed using EQR variant. Our results support the potential applicability of Cpf1 in precision medicine through highly specific inactivation of many other gain-of-function mutations.

In this study, we electrospun novel poly(propylene carbonate)/poly(ε-caprolactone) (PPC/PCL) nanofibers with a special nanoscale topography using a simple process. The characteristics of the fabricated scaffolds were investigated using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction analyses (XRD), thermogravimetric analyses (TG), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), water contact angle measurements (WCA), tensile tests and Brunauer–Emmett–Teller (BET) surface area analysis. To determine whether the nanoscale topography altered mesenchyme stem cell adhesion proliferation and differentiation behavior, adipose tissue-derived stromal cells (ADCs) were cultured on pure PPC electrospun scaffolds with smooth nanotopography and PPC/PCL (20 wt% PCL) hybrid scaffold with nanoscale topography. The results reveal that PPC/PCL electrospun fibers with special inter-surface-connected pores possess a high BET surface area and could promote ADCs adhesion and proliferation. According to alizarin red S staining and von-Kossa staining assays, there are more calcium nodule deposits on scaffolds with inter-surface-connected pores.

Colorectal peritoneal carcinomatosis (CRPC) is a common form of systemic metastasis of intra-abdominal cancers, occurring in as many as 50% of colon cancer patients, and is associated with a poor prognosis. For the treatment of CRPC, cytoreductive surgery alone is inadequate at the microscopic level, and systemic chemotherapy has a limited effect due to the peritoneal-plasma barrier. Intraperitoneal chemotherapy is logically proposed early after surgery to treat the residual small and microscopic tumors. Traditional chemotherapy is typically infused intravenously. However, intraperitoneal chemotherapy allows direct contact of anti-cancer agents with tumor cells, which could improve tumor regression efficacy and minimize systemic toxicity. Furthermore, injectable and thermosensitive polymer hydrogels have shown promising applications as controlled drug delivery systems for in situ chemotherapy. In this study, a biodegradable thermogelling block copolymer poly(L-lactide acid)–Pluronic L35–poly(L-lactide acid) (PLLA–L35–PLLA) was synthesized to fabricate a novel local drug delivery system (DOC-M/OXA-H) composed of docetaxel loaded micelles (DOC-M) and an oxaliplatin loaded hydrogel (OXA-H). DOC, a widely used anticancer drug with extremely high hydrophobicity, was loaded into the biodegradable copolymer micelles by the membrane dialysis method without using any surfactants or excipients. And DOC-M was encapsulated in OXA-H to achieve the aim of synergistic combination therapy with significantly high efficacy and good patient compliance. As a result, DOC-M/OXA-H was an injectable flowing sol at ambient temperature and became a solid-like gel at physiological temperature without any crosslinking agent. Meanwhile, DOC-M/OXA-H demonstrated a slow and sustained drug release profile and the combination therapy of DOC and OXA exhibited quite potent cytotoxicity in vitro. Furthermore, an in vivo antitumor test with CRPC-bearing mice suggested that DOC-M/OXA-H was more competent for suppressing tumor growth and prolonging survival time by inhibiting tumor cell proliferation and angiogenesis and increasing apoptosis of tumor cells. Overall, our data suggested that DOC-M/OXA-H may be potentially useful in the treatment of CRPC.