Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.

Funder: KCL PhD scholarshipsFunder: Leverhulme Trust; Id: http://dx.doi.org/10.13039/501100000275Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer

Multi-antigen avian influenza a (H7N9) virus-like particles: particulate characterizations and immunogenicity evaluation in murine and avian models

Abstract Background Human infection with avian influenza A virus (H7N9) was first reported in China in March 2013. Since then, hundreds of cases have been confirmed showing severe symptoms with a high mortality rate. The virus was transmitted from avian species to humans and has spread to many neighboring areas, raising serious concerns over its pandemic potential. Towards containing the disease, the goal of this study is to prepare a virus-like particle (VLP) that consists of hemagglutinin (HA), neuraminidase (NA) and matrix protein 1 (M1) derived from the human isolate A/Taiwan/S02076/2013(H7N9) for potential vaccine development. Results Full length HA, NA, and M1 protein genes were cloned and expressed using a baculoviral expression system, and the VLPs were generated by co-infecting insect cells with three respective recombinant baculoviruses. Nanoparticle tracking analysis and transmission electron microscopy were applied to verify the VLPs\u2019 structure and antigenicity, and the multiplicity of infection of the recombinant baculoviruses was adjusted to achieve the highest hemagglutination activity. In animal experiments, BALB/c mice and specific-pathogen-free chickens receiving the VLP immunization showed elevated hemagglutination inhibition serum titer and antibodies against NA and M1 proteins. In addition, examination of cellular immunity showed the VLP-immunized mice and chickens exhibited an increased splenic antigen-specific cytokines production. Conclusions The H7N9 VLPs possess desirable immunogenicity in vivo and may serve as a candidate for vaccine development against avian influenza A (H7N9) infection

Targeting and Enrichment of Viral Pathogen by Cell Membrane Cloaked Magnetic Nanoparticles for Enhanced Detection

Attachment to cellular surfaces is a major attribute among infectious pathogens for initiating disease pathogenesis. In viral infections, viruses exploit receptor–ligand interactions to latch onto cellular exterior prior to subsequent entry and invasion. In light of the selective binding affinity between viral pathogens and cells, nanoparticles cloaked in cellular membranes are herein employed for virus targeting. Using the influenza virus as a model, erythrocyte membrane cloaked nanoparticles are prepared and modified with magnetic functionalities (RBC-mNP) for virus targeting and isolation. To maximize targeting and isolation efficiency, density gradient centrifugation and nanoparticle tracking analysis were applied to minimize the presence of uncoated particles and membrane vesicles. The resulting nanoparticles possess a distinctive membrane corona, a sialylated surface, and form colloidally stable clusters with influenza viruses. Magnetic functionality is bestowed to the nanoparticles through encapsulation of superparamagnetic iron-oxide particles, which enable influenza virus enrichment via magnetic extraction. Viral samples enriched by the RBC-mNPs result in significantly enhanced virus detection by multiple virus quantification methods, including qRT-PCR, immunnochromatographic strip test, and cell-based titering assays. The demonstration of pathogen targeting and isolation by RBC-mNPs highlights a biologically inspired approach toward improved treatment and diagnosis against infectious disease threats. The work also sheds light on the efficient membrane cloaking mechanism that bestows nanoparticles with cell mimicking functionalities