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As novel amphiphilic materials, six uncharged alkyl rhamnosides incorporating various alkyl chain and one rhamnose amine quaternary ammonium salt were successfully synthesized in this study. Their amphiphilic properties (HLB and CMC), antimicrobial and anti-biofilm activity against S. aureus and P. aeruginosa were investigated. Differentially regulated proteins and pathways were identified by comparative proteomics research to first give a sight on how alkyl rhamnosides performed the anti-biofilm activity at protein and pathway levels. Among the uncharged alkyl rhamnosides, dodecyl rhamnoside and octyl rhamnoside showed the best antimicrobial and anti-biofilm ability against S. aureus and against P. aeruginosa, respectively. Interestingly, the relationships between amphiphilic properties or MIC with anti-biofilm activity were first established. Uncharged alkyl rhamnoside with an optimized HLB value of 5.0 had both the strongest antibacterial and anti-biofilm activity against S. aureus, and MIC was the maximum biofilm inhibitory concentration for all alkyl rhamnosides. Alkyl rhamnosides have a significant overall regulatory effect on the proteomics and pathways of bacterial biofilms, including energy production, substrates transportation, signal transduction, key molecules balance, and so on. These amphiphilic materials have a great potential to be used as additives in pharmaceutic, cosmetic, food industry, hospital and in other non-medical fields. [ABSTRACT FROM AUTHOR]

Sirolimus is recognized as a P-glycoprotein (P-gp) substrate with poor water-solubility. To improve its solubility and bioabsorption, self-microemulsifying drug delivery systems (SMEDDS) containing a novel P-gp inhibitor, honokiol, were prepared. The aim of this work was to evaluate the enhanced transport of sirolimus SMEDDS as well as the roles of honokiol.In situsingle-pass intestinal perfusion andin vitrohuman colon adenocarcinoma (Caco-2) cell models were applied to study the effects of honokiol within SMEDDS on the transport of sirolimus. The results indicated that a combination of honokiol with sirolimus in SMEDDS did not significantly alter the particle size, polydispersity index and release of drugs. In addition, the absorption rate constant (Ka) as well as the effective permeability coefficients (Peff) of sirolimusin situintestinal absorption, and the apparent permeability coefficients (Papp) of sirolimus in caco-2 cells were significantly enhanced by cremophor EL-based SMEDDS with honokiol as compared with those of SMEDDS without honokiol. Rhodamine123 uptake rate in caco-2 cells andin vitrocytotoxicity of sirolimus were enhanced by honokiol in SMEDDS indicating a substantial P-gp inhibition of honokiol. In conclusion, coadministration of honokiol with poor soluble P-gp substrate in SMEDDS, could serve as a favorable approach for oral delivery. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to prepare wheat germ agglutinin (WGA)-modified liposomes encapsulating clarithromycin and to evaluate their in vitro and in vivo efficacy against Methicillin-resistant Staphylococcus aureus (MRSA). Methods: Physicochemical parameters, minimum inhibitory concentrations, in vitro killing kinetic, cellular uptake, biofilm formation inhibition and pre-formed biofilm destruction, biodistribution, in vivo antibacterial efficacy against MRSA, and phagocytosis into macrophages for liposomes loading clarithromycin were determined. Results: The minimum inhibitory concentration and the time-kill curve for WGA-modified liposomal clarithromycin were better than those of free and nonmodified liposomal clarithromycin. Flow cytometry analysis displayed that liposomes could deliver more Coumarin 6, a fluorescent probe, into bacteria because of the conjugation of WGA. Besides, WGA-modified liposomal clarithromycin inhibited formation of S. aureus (ATCC 29213) and MRSA biofiom, and prompted the biofilm disassembly at lower concentrations below MIC. Effective accumulation of liposomes was displayed in the enterocoelia of the mice because of WGA. The number of MRSA colony-forming units in the kidney and spleen in mice treated with WGA-modified liposomal clarithromycin was significantly lower than that treated with free and nonmodified clarithromycin ( p < 0.05). Intracellular localization of MRSA occurred in a significantly higher proportion of macrophage exposed to WGA-modified liposomes compared to those exposed to nonmodified liposomes. Conclusions: Liposome modified by WGA is a promising formulation for bacteria targeted delivery and immunity defensive system through macrophage improving uptake of bacteria, biodistribution, in vitro and in vivo antibacterial efficacy against MRSA. [ABSTRACT FROM AUTHOR]

Objectives The aims of the present study were to design polymeric micelles loading sirolimus with honokiol to increase drug solubility and to gain an insight into the effect of honokiol on oral transport of P-glycoprotein substrate (P-gp). Methods Particle size distribution, encapsulation efficiency, drug-loading content and in-vitro release of sirolimus-loaded micelles with honokiol were determined. Transport of sirolimus-loaded micelles across Caco-2 cell monolayers and jejunum segment of rats were investigated. In-vitro cytotoxicity experiments and the cellular uptake study were carried out via sulforhodamine B assay and flow cytometry, respectively. Key findings A coadministration of honokiol with sirolimus in micelles did not significantly modify the particle size, polydispersity index and release of drugs demonstrating successful loading within the micelles. The apparent transport coefficients (Papp) and effective permeability (Peff) of sirolimus were increased with more amount of honokiol loaded in micelles. Cellular uptake study demonstrated that rhodamine123 uptake rate was enhanced by honokiol-loaded micelles, indicating substantial P-gp inhibition action by honokiol and mPEG-PLA-based micelles. Conclusion Oral transport of sirolimus was significantly improved by coadministration with honokiol, an inhibitor of the P-gp, in polymeric micelles formulation. [ABSTRACT FROM AUTHOR]

Genetic and rare diseases (GARDs) affect more than 350 million patients worldwide and remain a significant challenge in the clinic. Hence, continuous efforts have been made to bridge the significant gap between the supply and demand of effective treatments for GARDs. Recent decades have witnessed the impressive progress in the fight against GARDs, with an improved understanding of the genetic origins of rare diseases and the rapid development in gene therapy providing a new avenue for GARD therapy. RNA-based therapeutics, such as RNA interference (RNAi), messenger RNA (mRNA) and RNA-involved genome editing technologies, demonstrate great potential as a therapy tool for treating genetic associated rare diseases. In the meantime, a variety of RNA delivery vehicles were established for boosting the widespread applications of RNA therapeutics. Among all the RNA delivery platforms which enable the systemic applications of RNAs, non-viral RNA delivery biomaterials display superior properties and a few biomaterials have been successfully exploited for achieving the RNA-based gene therapies on GARDs. In this review article, we focus on recent advances in the development of novel biomaterials for delivery of RNA-based therapeutics and highlight their applications to treat GARDs. [ABSTRACT FROM AUTHOR]

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol‐amino‐phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP‐derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self‐amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC‐0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs–saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation. [ABSTRACT FROM AUTHOR]

The goal is to develop anin situgel system comprising anionic liposomes (AL) containing bleomycin A6 (BLM A6) dispersed within the thermosensitivein situgel for sustained release. The results indicated that the gelation temperature decreased due to AL within gel. Similarly, viscosity and mechanical parameters, such as gel strength for gel, could be enhanced by inducing lipid material with negative charge (phosphatidylglycerol) at 37 °C, which provided against corrosion at physiological condition. Thein vitrorelease experiments performed with a dialysis method revealed thatin situgel with AL exhibited the longer drug-release period compared to that with or without nonionic liposomes. Anin vivofluorescence imaging study suggested that the gel with AL loading FITC-BLM A6 stayed in administration site at least for five days. A thermosensitivein situgel with anionic liposome was a promising carrier for hydrophilic BLM A6, to be used in parenteral delivery system for anti-tumor treatment. [ABSTRACT FROM PUBLISHER]

Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood–brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10–oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model. [ABSTRACT FROM AUTHOR]

Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8+ T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N- acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4 , antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC 50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment. [ABSTRACT FROM AUTHOR]