Development of a stable and high loaded liposomal formulation of lapatinib with enhanced therapeutic effects for breast cancer in combination with Caelyx®: In vitro and in vivo evaluations.

Lapatinib, a dual tyrosine kinase inhibitor, has poor water solubility, which results in poor and incomplete absorption from the gastrointestinal tract. To overcome this obstacle, we designed a stable and high-loaded liposomal formulation encapsulating lapatinib and examined its therapeutic efficacy in vitro and in vivo on TUBO and 4T1 cell lines. We also assessed the impact of liposomal lapatinib on the extent of the tumor and spleen-infiltrating lymphocytes and the autophagy and apoptosis gene expression within the tumor site. Our results showed that liposomal lapatinib inhibits cell proliferation and significantly induces autophagy and apoptosis compared to control groups. Moreover, when it used in combination with liposomal doxorubicin, it extended the time to end from 22.4 ± 3.5 in the control group to 40 days in the TUBO cell line and from 29.2 ± 1.7 to 38.6 ± 2.2 days in 4T1 triple-negative breast cancer cell line, which reveals its promising effects on the survival of tumor-bearing mice. Our results indicated the need for further evaluations to understand liposomal lapatinib's potential effects on autophagy, apoptosis, and particularly on immune system cells.

Development, characterization and evaluation of topical methotrexate-entrapped deformable liposome on imiquimod-induced psoriasis in a mouse model.

The aim of this study was to prepare and characterize topical methotrexate (MTX) with different percentages (0.05%, 0.1%, 0.25% and 0.5%) entrapped in deformable liposomes using phosphatidylcholine and oleic acid. The effectiveness and sub-acute toxicity of these topical formulations were investigated in imiquimod (IMQ)-induced psoriasis in a mouse model (IMQP). The particle sizes of formulations were around 100 nm with a mean zeta potential of -72.87 mV. The entrapment efficiency (EE%) of MTX in liposomal formulations were more than 85%. Franz cell permeability studies indicated that permeation of MTX through the healthy BALB/c mice skin is very low; however, in the inflammatory skin, which was induced by IMQ it was significant (50%). Liposomal MTX (LM 0.05 and 0.1%) caused significant reduction of thickness score dose-dependently in IMQP compared to the injected MTX. Moreover, investigation of the inflammatory factor and pathological examinations of skin proved the superiority of the LM treating group. Pathological examinations also showed there are no toxicity in organs of the mice that received the LM. Blood cell count test didn't show any abnormality. MTX-entrapped deformable liposomes could be a topical option in future for the treatment of human psoriasis with a less toxicity and merit further investigations.

Interactive anticancer effect of nanomicellar curcumin and galbanic acid combination therapy with some common chemotherapeutics in colon carcinoma cells.

OBJECTIVE: In the current investigation, we aimed to study the combined cytotoxicity of curcumin, as a nanomicellar formulation, and galbanic acid (Gal), dissolved in DMSO against the murine C26 and human Caco-2 colon carcinoma cells. Further, curcumin potential for cisplatin and doxorubicin (Dox) co-therapy was studied. MATERIALS AND METHODS: The combined cytotoxic effect of these phytochemicals at varying dose ratios were examined using the MTT colorimetric assay. Moreover, the time-dependent toxicity of curcumin, cisplatin, Dox, and pegylated liposomal Dox (Doxil) was determined. The interactive anti-proliferative behavior of these compounds was examined using the CompuSyn software. RESULTS: Nanomicellar curcumin showed considerable cytotoxicity in C26 cells 24 hr post-treatment. Co-treatment of cells with curcumin nanomicelles: Gal had a synergistic effect in C26 (at 10:1 molar ratio), and Caco-2 (at 1:5 molar ratio) cell lines in cell cultures. Nanomicellar curcumin showed strong and mild synergistic inhibitory effects in C26 cells when co-administered with Doxil and cisplatin, respectively. CONCLUSION: Curcumin nanomicelles and Gal had a synergistic effect in C26 and Caco-2 cell lines. It is speculated that nanomicellar curcumin shows synergistic cancer cell killing if administered 24-hr post-injection of Doxil and cisplatin.

The role of nanoliposome bilayer composition containing soluble leishmania antigen on maturation and activation of dendritic cells.

OBJECTIVES: Dendritic cells (DCs) play a critical role in activation of T cell responses. Induction of type1 T helper (Th1) immune response is essential to generate protective immunity against cutaneous leishmaniasis. The intrinsic tendency of liposomes to have interaction with antigen-presenting cells is the main rationale to utilize liposomes as antigen carriers. In the present study, the effect of lipid phase transition temperature on DCs maturation and liposome uptake by murine bone marrow derived dendritic cells and human monocyte derived dendritic cells was investigated. MATERIALS AND METHODS: Two cationic liposomal formulations consisting of DOTAP and DSPC/DOTAP were prepared and contained soluble leishmania antigen. Liposomes were incubated with immature or mature DCs derived from bone marrow (BMDCs) of C57BL/6 (which are resistant to cutaneous leishmaniasis), BALB/c mice (susceptible to cutaneous leishmaniasis) or DCs derived from human monocytes (MoDCs). The expression of DCs co-stimulatory markers and liposomal uptake were evaluated by flow cytometry method. RESULTS: DCs which were encountered to liposomes consisting of DSPC showed significantly more expression of co-stimulatory molecules in cells from both human and C57BL/6 mice but not in cells from BALB/c mice. CONCLUSION: It is concluded that cationic liposomes consisting of DSPC are an effective adjuvant for antigen delivery in case of MoDCs and BMDCs from C57BL/6 mice. Moreover, DCs from different origins act differently in uptake of liposomes.

Protective Effects of Vitamin C and NAC on the Toxicity of Rifampin on Hepg2 Cells.

Rifampin, an antibiotic widely used for the treatment of mycobacterial infections, produces hepatic, renal and bone marrow toxicity in human and animals. In this study, the protective effects of vitamin C and n-acetylcysteine (NAC) on the toxicity of rifampin on HepG2 cells were investigated. Human hepatoma cells (HepG2) were cultured in 96-well M of rifampin in the presence of microplate and exposed to 10, 20, 50 and 100 vitamin C (0.1 mg/mL) and NAC (0.2 mg/mL). Protective effect of the two drugs against rifampin toxicity was assessed by MTT assay. Results show that both vitamin C and NAC significantly inhibited HepG2 cellular damage due to rifampin, and vitamin C was relatively more potent than NAC. Rifampin is metabolized by the liver and its toxic metabolites are responsible for the drug>s hepatic toxicity. Based on our results, it seems that reactive metabolites are the main agents responsible for rifampin hepatotoxicity. The importance of this finding is that if vitamin C or NAC do not affect the antibacterial activity of rifampin, they could be used as preventive agents in rifampin users.

Efficacy of Topical Liposomal Amphotericin B versus Intralesional Meglumine Antimoniate (Glucantime) in the Treatment of Cutaneous Leishmaniasis.

Background. Topical treatment of cutaneous leishmaniasis is an attractive alternative avoiding toxicities of parenteral therapy while being administered through a simple painless route. Recently liposomal formulations of amphotericin B have been increasingly used in the treatment of several types of leishmaniasis. Aims. The efficacy of a topical liposomal amphotericin B formulation was compared with intralesional glucantime in the treatment of cutaneous leishmaniasis. Methods. From 110 patients, the randomly selected 50 received a topical liposomal formulation of amphotericin B into each lesion, 3-7 drops twice daily, according to the lesion's size and for 8 weeks. The other group of 60 patients received intralesional glucantime injection of 1-2 mL once a week for the same period. The clinical responses and side effects of both groups were evaluated weekly during the treatment course. Results. Per-protocol analysis showed no statistically significant difference between the two groups (P = 0.317, 95% confidence interval (CI) = 1.610 (0.632-4.101)). Moreover, after intention-to-treat analysis, the same results were seen (P = 0.650, 95% CI = 0.1.91 (0.560-2.530)). Serious post treatment side effects were not observed in either group. Conclusions. Topical liposomal amphotericin B has the same efficacy as intralesional glucantime in the treatment of cutaneous leishmaniasis.

Characterization, blood profile and biodistribution properties of surface modified PLGA nanoparticles of SN-38.

SN-38, the active metabolite of irinotecan, poses a challenge in terms of drug delivery due to its low solubility and labile lactone ring. The aim of this study was to develop a SN-38 nanoparticulate delivery system to evaluate the in vivo blood profile and biodistribution properties of nanoparticles (NPs). Poly lactide-co-glycolide (PLGA) NPs that were covalently bound to polyethylene glycol-folate (PEG-FOL) were prepared, and their in vivo biodistribution in rats was investigated. Either the SN-38 solution or SN-38 NP suspension was administered intravenously into the tail vein at a dose of 2mg SN-38 eq./kg. As expected, SN-38 NPs showed a higher plasma concentration in vivo when compared with free SN-38 during a 24h period. Compared with the SN-38 solution, both folate targeted and non-targeted NPs exhibited superior drug concentration in body organs such as the liver, spleen, and lung at 1 and 8h post-administration.