Evaluation of Immune Response against Leishmaniasis in BALB/c Mice Immunized with Cationic DOTAP/DOPE/CHOL Liposomes Containing Soluble Leishmania major Antigens

Background: Whole killed Leishmania vaccine reached phase III clinical trials but failed to display significant efficacy in human mainly due to limited Th1 inducer adjuvant. Liposomes consisting of 1, 2-dioleoyl-3trimethylammonium-propane (DOTAP) bearing an inherent adjuvanticity and 1, 2-dioleoyl-L-α-glycero-3-phosphatidylethanolamine (DOPE) is well known to intensify the efficacy of positively charged liposomes. Methods: Soluble Leishmania major antigens (SLA) encapsulated in cationic liposomes using lipid film method in 2016). BALB/c mice were immunized subcutaneously (SC), three times in a 2-wk interval, with Lip (DOTAP)-SLA+, Lip (DOTAP/DOPE)-SLA+, Lip (DOTAP/DOPE/CHO)-SLA+, Lip (DOTAP/DOPE/CHO), Lip (DOPE/CHO), SLA or HEPES buffer. At week 2 after the last booster injection, immunized mice have challenged SC in the footpad with L. major parasites. To investigate the rate of protection and the type of immune response generated in mice, lesions development was assessed, IL-4 and IFN-γ levels with the ratio of IgG2a/IgG1 isotype were studied to describe the type of generated immune response. Results: Mice immunized with all liposomal form of SLA showed smaller footpad swelling and lower parasite burden in the spleen and footpad compared to the group of mice received buffer. However, these formulations did not show protection against leishmaniosis because of a generated mixed Th1/Th2 response in mice characterized by high production of IFN-γ and IL4 and a high titer of IgG1 and IgG2a antibody. Conclusion: Immunization with Lip (DOTAP/DOPE/CHO)-SLA+ was not an appropriate strategy to protect mice against leishmaniosis

Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer

Objective(s): P-glycoprotein (P-gp) is an efflux protein, the overexpression of which has been associated with multidrug resistance in various cancers. Although siRNA delivery to reverse P-gp expression may be promising for sensitizing of tumor cells to cytotoxic drugs, the therapeutic use of siRNA requires effective carriers that can deliver siRNA intracellularly with minimal toxicity on target cells. We investigated a special class of PEGylated lipid-based nanoparticles (NP), named nanolipoparticles (NLPs), for siRNA- mediated P-gp downregulation. Materials and Methods: NLPs were prepared based on low detergent dialysis method. After characterization, we evaluated the effect of NLPs on siRNA delivery, and P-gp downregulation compared to oligofectamineTM (OFA) in vitro and in vivo. Results: Our results showed a significant decrease in P-gp expression and subsequent enhancement of chemosensitivity to doxorubicin in vitro. Although the effectiveness of NLPs for in vitro siRNA delivery compared to OFA was limited, the results of in vivo studies showed noticeable effectiveness of NLPs for systemic siRNA delivery. siRNA delivery using NLPs could downregulate MDR1 in tumor cells more than 80%, while OFA had a reverse effect on MDR1 expression in vivo. Conclusion: The results indicated that the prepared NLPs could be suitable siRNA delivery systems for tumor therapy

Applications of biomimetic nanoparticles in breast cancer as a blueprint for improved next-generation cervical cancer therapy

Nanomedicines are innovative and promising, but lack a convincing clinical presence. Thus, biomimetic nanoparticles (BMNPs) have been designed with functionalizations which structurally and/or functionally mimic the biological setting, endowing thereupon biological structure and functionality. These may be coated with biologically derived materials, but may also include artificial antigen-presenting cells and synthetic architectures. When applied in cancer theranostics, BMNPs show significant improvements over traditional drugs and similar non-biomimetic NPs, especially in terms of circulation time, tissue penetration, delivery, and lowered toxicity. These particles have achieved unprecedented outcomes through top-down synthesis methods (cell material to NP), which bypass complex bottom-up synthetic techniques attempting to mimic such complex and diverse biological components. Breast cancer has received much attention in this area, and as such, is studied in this paper as a template for how BMNPs could be applied in cervical cancer – an area with few BMNP applications and a dire need for efficacious and fertility-preserving therapies. This cancer remains an enormous burden globally, especially in developing countries. Being a virus-induced disease, biomimetic applications may be particularly promising, aligning with the emergence of biomimetic nanovaccines in recent years. Feasibility challenges remain within BMNPs: Extracting biological material for re-administration to patients could cause ethical debate, and the costs involved in preparing scaled up quantities of biomimetic NPs would be large. However, with a clearer understanding and tighter characterization of preparation methods and biological responses, BMNPs may add great value to the nanomedicine community.</p

Novel nanomicelle formulation to enhance bioavailability and stability of curcuminoids

Objective(s): Curcuminoids, comprising curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), are bioactive phytochemicals with numerous pharmacological effects. Oral biological availability of curcuminoids is low due to the low aqueous solubility and rapid metabolism. This study aimed at fabricating a nanomicellar curcuminoid formula with enhanced pharmacokinetic properties. Materials and Methods: Curcuminoids nanomicelles were prepared and characterized regarding particle properties, stability, release profile and pharmacokinetic parameters.Results: Encapsulation efficiency of curcuminoids in nanomicelles were 100%. Particle size analysis demonstrated a mean size of around 10 nm that remained stable for 24 months. Dissolution test showed the complete dissolution of encapsulated curcuminoids from nanomicelles within 20 min while the free curcuminoids were poorly dissolved (approximately 7% after 60 min). The results of long-term (24 months) and accelerated (6 months) stability studies showed no changes in the size and content of nanomicelles. The release studies in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) showed no release of curcuminoids for at least 4 hours. In vivo study in BALB/c mice showed improved pharmacokinetic parameters including maximum plasma concentration (Cmax) and time to reach the maximum concentration (Tmax) with nanomicelles as compared to free curcuminoids and two other commercial products. Tmax for all the three curcuminoid components was observed 30 min following oral administration. AUC of nanomicellar curcuminoids was 59.2 times more than free  curcuminoids. Conclusion: These data indicated that nanomicelles could improve solubility, oral bioavailability and also the stability of curcuminoids. Thus, they merit further investigation for enhancing pharmacological effects of curcuminoids

COMPARATIVE EFFICACY OF 1% CURCUMIN NANOMICELLE GEL AND 2% CURCUMIN GEL FOR TREATMENT OF RECURRENT APHTHOUS STOMATITIS: A DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL

Objective: Recurrent aphthous stomatitis (RAS) is a highly prevalent painful inflammatory condition. Curcumin is currently used as a medicinal herb with optimal anti–inflammatory properties for many inflammatory conditions. However, due to its low water solubility and consequently low bioavailability, its nanoparticulate formulation has been considered for use. This study aimed to compare the efficacy of topical application of 1% curcumin nanomicelle gel and 2% curcumin gel for treatment of RAS. Methods: This double-blind randomized clinical trial evaluated 48 RAS patients. The patients randomly received 1% curcumin nanomicelle gel or 2% curcumin gel, and were asked to apply it 3 times/day for 1 week. The severity of pain was measured using a visual analog scale (VAS), and the size of lesions (in millimeters) was measured by a periodontal probe before (baseline), and at 4, and 7 days after treatment. Data were analyzed by repeated measures ANOVA. Results: No significant difference was noted in the pain score (P = .160) or size of lesions (P = .432) between the 2 groups at baseline. At 7 days, the pain score and size of lesions significantly decreased in both groups (P < .05). The reduction in pain score and lesion size was significantly greater in the curcumin nanomicelle gel group at both 4 and 7 days (P < .05). Also, the efficacy index (EI) was higher in curcumin nanomicelle gel group. Conclusions: The 1% curcumin nanomicelle gel can be effectively used to enhance the healing of RAS. Keywords: Recurrent aphthous stomatitisTreatmentNano-curcuminCurcumi

The effect of berberine nanomicelles on hepatic cirrhosis in bile duct-ligated rats

Objective (s): The anti-fibrotic effect of chronic berberine (BBR) had demonstrated previously in a rat model of bile duct ligation (BDL). The aim of present study was to investigate hepatoprotective effect of BBR nanomicelles on liver cirrhosis induced by BDL in male rats.Materials and methods: After 21 days of drugs’ treatments, the serum and tissue levels of hepatic markers were measured and pathologic evaluations performed.Results: BDL could markedly increase aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH, and total bilirubin (TBIL) serum levels and tissue tumor necrosis factor-alpha (TNF-α) level along with reductions in tissue levels of key antioxidants glutathione (GSH) and superoxide dismutase (SOD) as well as total protein. On the other hand, silymarin (100 mg/kg, p.o.), BBR (100 mg/kg) and BBR nanomicelles (50 mg/kg, p.o.) markedly decreased AST and ALT while enhanced GSH. In addition, BBR nanomicelles (50 mg/kg, p.o.), silymarin (100 mg/kg, p.o.) and BBR (100 mg/kg, p.o.) groups showed a considerable increase in SOD. BBR nanomicelles (50 mg/kg, po.) significantly lowered TNF-α. In addition, nanoBBR treatment prevented liver cirrhosis in histopathologic analysis.Conclusion: Formulation of BBR may represent a worthy approach to enhance the effect of it in liver injuries

The Impact of Silymarin on the Symptom Severity in Pediatric Patients with Inflammatory Bowel Disease: A Randomized Clinical Trial

Background: Inflammatory Bowel Disease (IBD) is a multifactorial disease, posing significant challenges to public health. The aim of this study is to determine the effect of silymarin on the symptom severity in pediatric patients with IBD.Methods & Materials: This randomized clinical trial was conducted on children aged 5-18 diagnosed with IBD referred to the GI clinic at Akbar Children's Hospital in Mashhad. Those who met the inclusion criteria were randomly allocated into either the intervention or placebo group, each group consisting of 20 participants. In the intervention group, silymarin was administered three times daily in divided doses for three months. The control group received a placebo. To assess the efficacy of silymarin, PUCAI and PCDAI were evaluated for all patients at three different time points: before the intervention, during the first visit, and after the intervention. Data were analyzed utilizing the SPSS version 25, with a significance level set at p 0.05). However, a statistically significant difference was observed in the disease activity index score between the two groups during the second, and third evaluations (p<0.05)

Immunogenicity and antitumor activity of the superlytic λF7 phage nanoparticles displaying a HER2/neu-derived peptide AE37 in a tumor model of BALB/c mice

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.canlet.2018.03.030 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/Phage display technique has been increasingly researched for vaccine design and delivery strategies in recent years. In this study, the AE37 (Ii-Key/HER-2/neu 776–790) peptide derived from HER2 (human epidermal growth factor receptor protein) was used as a fused peptide to the lambda phage (λF7) coat protein gpD, and the phage nanoparticles were used to induce antitumor immunogenicity in a TUBO model of breast cancer in mice. Mice were immunized with the AE37 peptide displaying phage, λF7 (gpD::AE37) every 2-week intervals over 6-weeks, then the generated immune responses were evaluated. An induction of CTL immune response by the λF7 (gpD::AE37) construct compared to the control λF7 and buffer groups was observed in vitro. Moreover, in the in vivo studies, the vaccine candidate showed promising prophylactic and therapeutic effects against the HER2 overexpressing cancer in BALB/c mice.Mashhad University of Medical Sciences, Mashhad, Iran bach (MUMS GN: 922610)NSERC, Canada (NSERC GN: 214684