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miRNAs are promising therapeutic targets or tools for the treatment of numerous diseases, with most prominently, cancer. The inherent capacity of these short nucleic acids to regulate multiple cancer-related pathways simultaneously has prompted strong research on understanding miR functions and their potential use for therapeutic purposes. A key determinant of miR therapeutics’ potential for treatment is their delivery. Viral and non-viral vectors attempt to address the major limitations associated with miR delivery, but several hurdles have been identified. Here, we present an overview on the general limitations of miR delivery, and the delivery strategies exploited to overcome them. We provide an introduction on the advantages and disadvantages of viral and non-viral vectors, and we go into detail to analyze the most prominently used non-viral systems. We provide with an update on the most recent research on this topic and we describe the mechanism and limitations of the lipid-, polymer- and inorganic material- based miR delivery systems. [ABSTRACT FROM AUTHOR]

In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. From the Clinical Editor The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the influence of antigen entrapment in PLA nanoparticles on the immune responses obtained after transcutaneous immunization. OVA-loaded PLA nanoparticles were prepared using a double emulsion process. Following application onto bare skin of mice in vivo, fluorescence-labeled nanoparticles were detected in the duct of the hair follicles indicating that the nanoparticles can penetrate the skin barrier through the hair follicles. Although the OVA-loaded nanoparticles elicited lower antibody responses than those induced by OVA in aqueous solution they were more efficient in inducing cytokine responses. In vitro re-stimulation of cultured splenocytes with OVA elicited a little higher levels of IFN-γ (difference statistically insignificant, p >0.05) and significantly higher levels of IL-2 (p <0.001) in mice immunized with OVA-loaded nanoparticles compared to those immunized with OVA in solution. In the presence of CT, the OVA-loaded nanoparticles induced significantly higher IFN-γ and IL-2 than all other formulations. Transcutaneous administration of OVA encapsulated in the PLA nanoparticles exhibited priming efficacy to a challenging dose of OVA given via different route. These findings indicate the potential of nanoparticles to deliver antigens via the transcutaneous route and prime for antibody and strong cellular responses. The co-administration of an adjuvant such as CT had the added advantage of modulating the immune response, a desirable characteristic within the context of vaccination against intracellular versus extracellular pathogens. [Copyright &y& Elsevier]

Among the lung cancers, approximately 85% are histologically classified as non-small-cell lung cancer (NSCLC), a leading cause of cancer deaths worldwide. Epidermal growth factor receptors (EGFRs) are known to play a crucial role in lung cancer. HER2 overexpression is detected by immunohistochemistry in 2.4%–38% of NSCLC samples. EGFRs have been targeted with three generations of tyrosine kinase inhibitors (TKIs), and drug resistance has become a major issue; HER2 dimerization with EGFR also plays a major role in the development of resistance to TKI therapy. We have designed grafted peptides to bind to the HER2 extracellular domain (ECD) and inhibit protein-protein interactions of EGFR:HER2 and HER2:HER3. A sunflower trypsin inhibitor (SFTI-1) template was used to graft a peptidomimetic compound. Among several grafted peptides, SFTI-G5 exhibited antiproliferative activity in HER2-positive NSCLC cell lines such as Calu-3 cells with an IC 50 value of 0.073 μM. SFTI-G5 was shown to bind to ECD of HER2 and inhibit EGFR:HER2 and HER2:HER3 dimerization and inhibit the phosphorylation of HER2 and downstream signaling proteins. As a proof-of-concept, the in vivo activity of SFTI-G5 was evaluated in two NSCLC mouse models. SFTI-G5 was able to inhibit tumor growth in both models. Furthermore, SFTI-G5 was shown to inhibit EGFR dimerization in tissue samples obtained from in vivo models. These grafted peptides can be used as novel dual inhibitors of EGFR dimerization in NSCLC. [Display omitted] • A grafted peptide was designed to inhibit protein-protein interactions (PPI) of EGFRs. • The peptide binds to HER2 protein extracellular domain IV and inhibits PPI of EGFRs. • It was shown to inhibit the phosphorylation of HER2 kinase in vitro and in vivo. • The grafted peptide was able to inhibit tumor growth of NSCLC in mice model. • Stable grafted peptides can be used as therapeutic agents for NSCLC. [ABSTRACT FROM AUTHOR]

[Display omitted] • Peptide targeted liposomal formulations of drugs for cancer treatment are an effective approach. • A stable liposomal formulation with lyoprotectants with peptidomimetic-Dox conjugate was prepared. • A freeze-dried formulation of the liposome was evaluated for its stability. • The freeze-dried liposomal formulation was stable and targeted HER2 positive NSCLC. Nanocarrier-mediated administration of chemotherapeutic drugs can increase the therapeutic index of drugs by reducing off-target site toxicity. Ligand-targeted drug delivery can be utilized to deliver chemotherapeutic drugs to cancer cells selectively and specifically. Here we report the evaluation of a lyophilized formulation of a liposome containing a peptidomimetic-doxorubicin conjugate for targeted delivery of doxorubicin to HER2-positive cancer cells. The lyophilized liposomal formulation exhibited improved release of peptidomimetic-doxorubicin conjugate at pH 6.5 compared to 7.4 and improved cellular uptake in cancer cells at pH 6.5. In vivo studies indicated that pH-sensitive formulation exhibited site-specific formulation delivery and improved anticancer efficacy than free doxorubicin. The findings suggested that combining a lyophilized pH-sensitive liposomal formulation containing trehalose as lyoprotectant with a targeting ligand coupled cytotoxic agent is a potential method for cancer chemotherapy while maintaining long-term stability at 4 °C of the liposome formulation. [ABSTRACT FROM AUTHOR]

Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs. Postnatal ENSCs were isolated from 2 to 4 week-old mouse colon and cultured with 5-HT 4 receptor agonist (RS67506)-loaded liposomal nanoparticles. ENSCs were co-cultured with mouse colon explants in the presence of RS67506-loaded (n = 3) or empty nanoparticles (n = 3). ENSCs were also transplanted into mouse rectum in vivo with RS67506-loaded (n = 8) or blank nanoparticles (n = 4) confined in a thermosensitive hydrogel, Pluronic F-127. Neuronal density and proliferation were analyzed immunohistochemically. Cultured ENSCs gave rise to significantly more neurons in the presence of RS67506-loaded nanoparticles. Similarly, colon explants had significantly increased neuronal density when RS67506-loaded nanoparticles were present. Finally, following in vivo cell delivery, co-transplantation of ENSCs with 5-HT 4 receptor agonist-loaded nanoparticles led to significantly increased neuronal density and proliferation. We conclude that optimization of postnatal ENSCs can support their use in cell-based therapies for neurointestinal diseases. [ABSTRACT FROM AUTHOR]

Abstract: (E)-4-(Fullerenopyrrolidin-1-yl)-3-methylbut-2-enoic acid and its corresponding succinimidyl ester, readily obtained through Prato-type modification of C60, were used for the selective N-acylation of polyamines. The thus obtained conjugates were evaluated for their antioxidative and anti-inflammatory activity and their cytotoxicity was determined. Members of this family of compounds showed interesting anti-lipid peroxidation, anti-lipoxygenase and anti-inflammatory activity and comparable cytocompatibility to spermidine. [Copyright &y& Elsevier]