The association between oxidized low-density lipoprotein and cancer: An emerging targeted therapeutic approach?

Lipids play an important role in varying vital cellular processes including cell growth and division. Elevated levels of low-density lipoprotein (LDL) and oxidized-LDL (ox-LDL), and overexpression of the corresponding receptors including LDL receptor (LDLR), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and cluster of differentiation 36 (CD36), have shown strong correlations with different facets of carcinogenesis including proliferation, invasion, and angiogenesis. Furthermore, a high serum level of LOX-1 is considered as a poor prognostic factor in many types of cancer including colorectal cancer. Ox-LDL could contribute to cancer progression and metastasis through endothelial-to-mesenchymal transition (EMT) and autophagy. Thus, many studies have shed light on the significant role of ox-LDL as a potential therapeutic target for cancer therapy. In various repurposing approaches, anti-dyslipidemia agents, phytochemicals, autophagy modulators as well as recently developed ldl-like nanoparticles have been investigated as potential tumor therapeutic agents by targeting oxidized-LDL/LOX-1 pathways. Herein, we reviewed the role of oxidized-LDL and LOX-1 in cancer progression, invasion, metastasis, and also cancer-associated angiogenesis. Moreover, we addressed therapeutic utility of several compounds that proved to be capable of targeting the metabolic moieties in cancer. This review provides insights on the potential impact of targeting LDL and ox-LDL in cancer therapy and their future biomedical implementations.

The impact of phospholipids with high transition temperature to enhance redox-sensitive liposomal doxorubicin efficacy in colon carcinoma model.

In this study, we have developed a redox-sensitive (RS) liposomal doxorubicin formulation by incorporating 10,10'-diselanediylbis decanoic acid (DDA) organoselenium compound as the RS moiety. Hence, several RS liposomal formulations were prepared by using DOPE, HSPC, DDA, mPEG2000-DSPE, and cholesterol. In situ drug loading using a pH gradient and citrate complex yielded high drug to lipid ratio and encapsulation efficiency (100%) for RS liposomes. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell uptake and cytotoxicity, as well as therapeutic efficacy in BALB/c mice bearing C26 tumor cells. The formulations showed an average particle size of 200 nm with narrow size distributions (PDI < 0.3), and negative surface charges varying from -6 mV to -18.6 mV. Our study confirms that the presence of the DDA compound in liposomes is highly sensitive to hydrogen peroxide at 0.1% w/v, resulting in a significant burst release of up to 40%. The in vivo therapeutic efficacy study in BALB/c mice bearing C26 colon carcinoma confirmed the promising function of RS liposomes in the tumor microenvironment which led to a prolonged median survival time (MST). The addition of hydrogenated soy phosphatidylcholine (HSPC) with a high transition temperature (Tm: 52-53.5°C) extended the MST of our 3-component formulation of F14 (DOPE/HSPC/DDA) to 60 days in comparison to Caelyx (PEGylated liposomal Dox), which is not RS-sensitive (39 days). Overall, HSPC liposomes bearing RS-sensitive moiety enhanced therapeutic efficacy against colon cancer in vitro and in vivo. This achievement unequivocally underscores the criticality of high-TM phospholipids, particularly HSPC, in significantly enhancing liposome stability within the bloodstream. In addition, RS liposomes enable the on-demand release of drugs, leveraging the redox environment of tumor cells, thereby augmenting the efficacy of the formulation.

Novel liposomal glatiramer acetate: Preparation and immunomodulatory evaluation in murine model of multiple sclerosis.

The frequent administration rate required for Glatiramer acetate (GA), a first-line therapy for Multiple sclerosis (MS), poses patient compliance issues. Only a small portion of the subcutaneously administered GA is available for phagocytosis by macrophages, as most of it is hydrolyzed at its administration site or excreted renally. To unravel these hurdles, we have prepared liposomal formulations of GA through thin film-hydration method plus extrusion. The clinical and histopathological efficacy of GA-loaded liposomes were assessed in prophylactic and therapeutic manners on murine model of MS (experimental autoimmune encephalomyelitis (EAE)). The selected GA liposomal formulation showed favorable size (275 nm on average), high loading efficiency, and high macrophage localization. Moreover, administration of GA-liposomes in mice robustly suppressed the inflammatory responses and decreased the inflammatory and demyelinated lesion regions in CNS compared to the free GA with subsequent reduction of the EAE clinical score. Our study indicated that liposomal GA could be served as a reliable nanomedicine-based platform to hopefully curb MS-related aberrant autoreactive immune responses with higher efficacy, longer duration of action, fewer administration frequencies, and higher delivery rate to macrophages. This platform has the potential to be introduced as a vaccine for MS after clinical translation and merits further investigations.

Anti-tumor activity of silymarin nanoliposomes in combination with iron: In vitro and in vivo study.

Combination therapy represents a promising strategy in cancer management by reducing chemotherapy resistance and associated side effects. Silymarin (SLM) has been extensively investigated due to its potent antioxidant properties and demonstrated efficacy against cancer cells. Under certain conditions however, polyphenolic compounds may also exhibit prooxidant activity by elevating intracellular reactive oxygen species (ROS), which can harm the target cells. In this study, we hypothesized that the simultaneous administration of iron (Fe) could alter the antioxidant characteristic of SLM nanoliposomes (SLM Lip) to a prooxidant state. Hence, we first developed a SLM Lip preparation using lipid film method, and then investigated the anti-oxidant properties as well as the cytotoxicity of the liposomal preparation. We also explored the efficacy of concomitant administration of iron sucrose and SML Lip on the tumor growth and survival of mice bearing tumors. We observed that exposing cells to iron, and consecutive treatment with SLM Lip (Fe + SLM Lip) could induce greater toxicity to 4 T1 breast cancer cells compared to SLM Lip. Further, Fe + SLM Lip combination demonstrated a time-dependent effect on reducing the catalase activity compared to SLM Lip, while iron treatment did not alter cell toxicity and catalase activity. In a mouse breast cancer model, the therapeutic efficacy of Fe + SLM Lip was superior compared to SLM Lip, and the treated animals survived longer. The histopathological findings did not reveal a significant damage to the major organs, whereas the most significant tumor necrosis was evident with Fe + SLM Lip treatment. The outcomes of the present investigation unequivocally underscored the prospective use of Fe + SLM combination in the context of cancer therapy, which warrants further scrutiny.

Liposomal silymarin anti-oxidative and anti-apoptotic features in lung cells: An implication in cadmium toxicity.

BACKGROUND: Several metallic elements with high atomic weight and density are serious systemic toxicants, and their wide environmental distribution increase the risk of their exposure to human. Silymarin (SL), a polyphenol from milk thistle (Silybum marianum) plant has shown protective role against heavy metal toxicity. However, its low aqueous solubility and rapid metabolism limits its therapeutic potential in clinic. METHODS: We compared the role of silymarin nanoliposomes (SL-L) against cadmium (Cd) toxicity in normal MRC-5 and A 549 cancer cells. MRC-5 and A 549 cells exposed to Cd at 25 and 0.25 µM respectively, were treated with various non-toxic SL-L concentrations (2.5, 5, 10 µM) and cells viability, reactive oxygen species (ROS) generation, apoptosis and levels of cleaved PARP and caspase-3 proteins were determined following incubation. RESULTS: Results indicated that Cd exposure significantly increased apoptosis due to ROS generation, and showed greater toxicity on cancer cells compared to normal cells. While SL-L at higher concentrations (25 µM and higher) exhibits pro-apoptotic features, lower concentrations (10 and 2.5 µM for MRC-5 and A 549 cancer cells, respectively) played a protective and anti-oxidant role in Cd induced toxicity in both cells. Further, lower SL-L was required to protect cancer cells against Cd toxicity. In general, treatment with SL-L significantly improved cell survival by decreasing ROS levels, cleaved PARP and caspase-3 in both MRC-5 and A 549 cells compared to free silymarin. CONCLUSION: Results demonstrated that SL-L potential in protecting against Cd-induced toxicity depends on concentration-dependent antioxidant and anti-apoptotic balance.

Surface-modified cationic liposomes with a matrix metalloproteinase-degradable polyethylene glycol derivative improved doxorubicin delivery in murine colon cancer.

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.

Poly-γ-glutamic acid nanoparticles as adjuvant and antigen carrier system for cancer vaccination.

Vaccination is an innovative strategy for cancer treatment by leveraging various components of the patients' immunity to boost an anti-tumor immune response. Rationally designed nanoparticles are well suited to maximize cancer vaccination by the inclusion of immune stimulatory adjuvants. Also, nanoparticles might control the pharmacokinetics and destination of the immune potentiating compounds. Poly-γ-glutamic acid (γ-PGA) based nanoparticles (NPs), which have a natural origin, can be easily taken up by dendritic cells (DCs), which leads to the secretion of cytokines which ameliorates the stimulation capacity of T cells. The intrinsic adjuvant properties and antigen carrier properties of γ-PGA NPs have been the focus of recent investigations as they can modulate the tumor microenvironment, can contribute to systemic anti-tumor immunity and subsequently inhibit tumor growth. This review provides a comprehensive overview on the potential of γ-PGA NPs as antigen carriers and/or adjuvants for anti-cancer vaccination.

Doxorubicin-loaded liposomes surface engineered with the matrix metalloproteinase-2 cleavable polyethylene glycol conjugate for cancer therapy.

Background: Colorectal cancer is one of the prominent leading causes of fatality worldwide. Despite recent advancements within the field of cancer therapy, the cure rates and long-term survivals of patients suffering from colorectal cancer have changed little. The application of conventional chemotherapeutic agents like doxorubicin is limited by some drawbacks such as cardiotoxicity and hematotoxicity. Therefore, nanotechnology has been exploited as a promising solution to address these problems. In this study, we synthesized and compared the anticancer efficacy of doxorubicin-loaded liposomes that were surface engineered with the 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-matrix metalloproteinase-2 (MMP-2) cleavable peptide-polyethylene glycol (PEG) conjugate. The peptide linker was used to cleave in response to the upregulated MMP-2 in the tumor microenvironment, thus exposing a positive charge via PEG-deshielding and enhancing liposomal uptake by tumor cells/vasculature. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell binding and uptake, and cytotoxicity. Results: The formulations had particle sizes of ~ 100-170 nm, narrow distribution (PDI ˂ 0.2), and various surface charges (- 10.2 mV to + 17.6 mV). MMP-2 overexpression was shown in several cancer cell lines (C26, 4T1, and B16F10) as compared to the normal NIH-3T3 fibroblast cells by gelatin zymography and qRT-PCR. In vitro results demonstrated enhanced antitumor efficacy of the PEG-cleavable cationic liposomes (CLs) as compared to the commercial Caelyx® (up to fivefold) and the chick chorioallantoic membrane assay showed their great antiangiogenesis potential to target and suppress tumor neovascularization. The pharmacokinetics and efficacy studies also indicated higher tumor accumulation and extended survival rates in C26 tumor-bearing mice treated with the MMP-2 cleavable CLs as compared to the non-cleavable CLs with no remarkable sign of toxicity in healthy tissues. Conclusion: Altogether, the MMP-2-cleavable CLs have great potency to improve tumor-targeted drug delivery and cellular/tumor-vasculature uptake which merits further investigation. Supplementary Information: The online version contains supplementary material available at 10.1186/s12645-023-00169-8.

Role of exosomes in tumour growth, chemoresistance and immunity: state-of-the-art.

Cancer is one of the most lethal diseases, and limited available treatment options contribute to its high mortality rate. Exosomes are considered membrane-bound nanovesicles that include different molecules such as lipids, proteins, and nucleic acids. Virtually most cells could release exosomes via exocytosis in physiological and pathological conditions. Tumour-derived exosomes (TDEs) play essential roles in tumorigenesis, proliferation, progression, metastasis, immune escape, and chemoresistance by transferring functional biological cargos, triggering different autocrine, and paracrine signalling cascades. Due to their antigen-presenting properties, exosomes are widely used as biomarkers and drug carriers and have a prominent role in cancer immunotherapy. They offer various advantages in carrier systems (e.g. in chemotherapy, siRNA, and miRNA), delivery of diagnostic agents owing to their stability, loading of hydrophobic and hydrophilic agents, and drug targeting. Novel exosomes-based carriers can be generated as intelligent systems using various sources and crosslinking chemistry extracellular vesicles (EVs). Exosomes studded with targeting ligands, including peptides, can impart in targeted delivery of cargos to tumour cells. In this review, we comprehensively summarised the important role of tumour-derived exosomes in dictating cancer pathogenesis and resistance to therapy. We have therefore, investigated in further detail the pivotal role of tumour-derived exosomes in targeting various cancer cells and their applications, and prospects in cancer therapy and diagnosis. Additionally, we have implicated the potential utility and significance of tumour exosomes-based nanoparticles as an efficient and novel therapeutic carrier and their applications in treating advanced cancers.

Redox-sensitive doxorubicin liposome: a formulation approach for targeted tumor therapy.

In this study redox-sensitive (RS) liposomes manufactured using 10,10'-diselanediylbis decanoic acid (DDA), an organoselenium RS compound, to enhance the therapeutic performance of doxorubicin (Dox). The DDA structure was confirmed by 1H NMR and LC-MS/MS. Various liposomal formulations (33 formulations) were prepared using DOPE, Egg PC, and DOPC with Tm Ë‚ 0 and DDA. Some formulations had mPEG2000-DSPE and cholesterol. After extrusion, the external phase was exchanged with sodium bicarbonate to create a pH gradient. Then, Dox was remotely loaded into liposomes. The optimum formulations indicated a burst release of 30% in the presence of 0.1% hydrogen peroxide at pH 6.5, thanks to the redox-sensitive role of DDA moieties; conversely, Caelyx (PEGylated liposomal Dox) showed negligible release at this condition. RS liposomes consisting of DOPE/Egg PC/DDA at 37.5 /60/2.5% molar ratio, efficiently inhibited C26 tumors among other formulations. The release of Dox from RS liposomes in the TME through the DDA link fracture triggered by ROS or glutathione is seemingly the prerequisite for the formulations to exert their therapeutic action. These findings suggest the potential application of such intelligent formulations in the treatment of various malignancies where the TME redox feature could be exploited to achieve an improved therapeutic response.

Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach.

Objectives: Brain cancer treatments have mainly failed due to their inability to cross the blood-brain barrier. Several studies have confirmed the presence of glutathione (GSH) receptors on BBB's surface, as a result, products like 2B3-101, which contain over 5% pre-inserted GSH PEGylated liposomal doxorubicin, are being tested in clinical trials. Here we conducted the PEGylated nanoliposomal doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. Compared with the pre-insertion approach, the post-insertion method is notably simpler, faster, and more cost-effective, making it ideal for large-scale pharmaceutical manufacturing. Materials and Methods: The ligands of the DSPE PEG(2000) Maleimide-GSH were introduced in the amounts of 25, 50, 100, 200, and 400 on the available Caelyx. Following physicochemical evaluations, animal experiments such as biodistribution, fluorescence microscopy, and pharmacokinetics were done. Results: In comparison with Caelyx, the 200L and 400L treatment arms were the most promising formulations. We showed that nanocarriers containing 40 times fewer GSH micelles than 2B3-101 significantly increased blood-brain barrier penetrance. Due to the expressed GSH receptors on tissues as an endogenous antioxidant, doxorubicin will likely concentrate in the liver, spleen, heart, and lung in comparison with Caelyx, according to other tissue analyses. Conclusion: The post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, further investigations are highly recommended to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus 2B3-101 as a similar formulation with a different preparation method.

Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: An implication in colorectal cancer therapy.

Cis-Diaminedichloroplatinum (cisplatin, CDDP) remained among the most widely used anti-cancer agents; however, management of the dose-limiting side effects is still a great hurdle to its therapeutic potential. In the framework of this investigation, novel approach was developed for CDDP encasement within liposome based on the formation of a coordination bond between the platinum (II) atom and a carboxylic group in aspartic acid (AA) and glutamic acid (GA). We have also compared two methods of preparation based on equilibration and conventional lipid film hydration. For this, first FTIR spectra of the conjugates confirmed coordination bond between Pt and the carboxylate moieties. The PEGylated liposomes composed of HSPC, cholesterol and DPPG had a size of 134 to 197 nm and negative zeta potential (-14.20 to -20.90 mv). Cytotoxicity study revealed IC50 values of <7 µg/ml for liposomes. In vivo plasma retention following iv administration indicated the potential of liposome in maintaining cisplatin levels within the circulation, while free cisplatin and cisplatin conjugates were promptly eliminated. Anti-tumor efficacy studies following iv injections at 3 mg/kg cisplatin weekly for three weeks in C26 tumor bearing BALB/c mice demonstrated the potential of the cisplatin liposomes in tumor growth inhibition. Pt-complexes were not as effective as liposomal formulations showing the crucial role of liposomes in maintaining cisplatin levels within blood circulation. Overall, the developed cisplatin liposome seems to be a promising therapeutic approach for targeting solid tumors.

Antisense technology as a potential strategy for the treatment of coronaviruses infection: With focus on COVID-19.

After the outbreak of coronavirus disease 2019 (COVID-19) in December 2019 and the increasing number of SARS-CoV-2 infections all over the world, researchers are struggling to investigate effective therapeutic strategies for the treatment of this infection. Targeting viral small molecules that are involved in the process of infection is a promising strategy. Since many host factors are also used by SARS-CoV-2 during various stages of infection, down-regulating or silencing these factors can serve as an effective therapeutic tool. Several nucleic acid-based technologies including short interfering RNAs, antisense oligonucleotides, aptamers, DNAzymes, and ribozymes have been suggested for the control of SARS-CoV-2 as well as other respiratory viruses. The antisense technology also plays an indispensable role in the treatment of many other diseases including cancer, influenza, and acquired immunodeficiency syndrome. In this review, we summarised the potential applications of antisense technology for the treatment of coronaviruses and specifically COVID-19 infection.

An insight into the role of liposomal therapeutics in the reversion of multiple sclerosis.

INTRODUCTION: Multiple Sclerosis (MS), as an autoimmune disease, has complicated immunopathology, which makes its management relevant to various factors. Novel pharmaceutical vehicles, especially liposomes, can support efficacious handling of this disease both in early detection and prognosis and also in a therapeutic manner. The most well-known triggers of MS onset are the predominance of cellular to humoral immunity and enhancement of inflammatory cytokines level. The installation of liposomes as nanoparticles to control this disease holds great promise up to now. AREAS COVERED: Various types of liposomes with different properties and purposes have been formulated and targeted immune cells with their surface manipulations. They may be encapsulated with anti-inflammatory, MS-related therapeutics, or immunodominant myelin-specific peptides for attaining a higher therapeutic efficacy of the drugs or tolerance induction. Cationic liposomes are also highly applicable for gene delivery of the anti-inflammatory cytokines or silencing the inflammatory cytokines. Liposomes have also been used as biotools for comprehending MS pathomechanisms or as diagnostic agents. EXPERT OPINION: The efforts to manage MS through nanomedicine, especially liposomal therapeutics, pave a new avenue to a high-throughput medication of this autoimmune disease and their translation to the clinic in the future for overcoming the challenges that MS patients confront.

pH-Sensitive PEGylated Liposomal Silybin: Synthesis, In Vitro and In Vivo Anti-Tumor Evaluation.

The drug delivery systems improve the efficacy of chemotherapeutics through enhanced targeting and controlled release however, biological barriers of tumor microenvironment greatly impede the penetration of nanomedicine within the tumor. We report herein the fabrication of a PEG-detachable silybin (SLB) pH-sensitive liposome decorated with TAT-peptide. For this, Acyl hydrazide-activated PEG2000 was prepared and linked with ketone-derivatized DPPE via an acid-labile hydrazone bond to form mPEG2000-HZ-DPPE. TAT peptide was conjugated with a shorter -PEG1000-DSPE spacer and post-inserted into PEGylated liposome (DPPC: mPEG2000-DSPE: Chol). To prepare nanoliposomes (around 100 nm), first, a novel method was used to prepare SLB-Soya PC (SLB-SPC) complex, then this complex was incorporated into nanoliposomes. The pH-sensitivity and shielding effect of long PEG chain on TAT peptide was investigated using DiI liposome and FACS analysis. Pre-treatment to the lowered pH enhanced cellular association of TAT-modified pH-sensitive liposome due to the cleavage of hydrazone bond and TAT exposure. Besides, TAT-modified pH-sensitive liposomes significantly reduced cell viability compared to the plain liposome. In vivo results were very promising with pH-sensitive liposome by detaching PEG moieties upon exposure to the acidic tumor microenvironment, enhancing cellular uptake, retarding tumor growth, and prolonging the survival of 4T1 breast tumor-bearing BALB/c mice. TAT modification of pH-sensitive liposome improved cancer cell association and cytotoxicity and demonstrated potential intracellular delivery upon exposure to acidic pH. However, in in vivo studies, TAT as a targeting ligand significantly decreased the therapeutic efficacy of the formulation attributed to an inefficient tumor accumulation and higher release rate in the circulation. The results of this study indicated that pH-sensitive liposome containing SLB, which was prepared with a novel method with a significant SLB loading efficiency, is very effective in the treatment of 4T1 breast tumor-bearing BALB/c mice and merits further investigation.

Redox-sensitive nanoscale drug delivery systems for cancer treatment.

Pharmaceutical nanotechnology introduces novel strategies in designing smart nanoscale drug delivery systems (NDDSs) capable of responding to specific conditions. These smart responsive NDDSs respond to specific conditions already established in the tumor microenvironment (TME) resulting in greater drug release following accumulation through enhanced permeation and retention (EPR) effect. Among various specific conditions, reactive oxygen species (ROS) and glutathione (GSH) have been extensively used to improve tumor targeting. While cells of the tumor microenvironment including immune cells, cancer-associated fibroblasts, endothelial cells and tumor invasive cells are responsible for the production and elevation of ROS levels, high levels of GSH inside tumor cells establish highly reducing environment, which in turn maintain cell survival. Abnormal ROS generation in the tumor microenvironment helps with designing highly specific ROS-sensitive NDDSs with the potential to release the payload next to the tumor cells. On the other hand, elevated levels of tumor GSH allows for designing NDDSs bearing reductively cleavable linkage to enhance drug release exploiting the dramatic higher intracellular GSH. The aim of the current review is to emphasize the requirements for developing various NDDSs including liposomes, polymeric nanoparticles, micelles, mesoporous silica nanoparticles, nanogels and prodrugs, capable of responding to TME using their Redox-sensitive moieties.

Development of a topical liposomal formulation of Amphotericin B for the treatment of cutaneous leishmaniasis.

BACKGROUND: Currently, there is no topical treatment available for any form of cutaneous leishmaniasis (CL) in most of the endemic areas. The aim of the current study was to develop a topical nano-liposomal Amphotericin B (AmB) for the treatment of CL. METHODOLOGY/PRINCIPAL FINDINGS: Liposomes containing 0.1, 0.2 and 0.4% AmB (Lip-AmB) were formulated and characterized for the size, entrapment efficiency, long term stability, and skin penetration properties using Franz diffusion cells. Liposomes diameters were around 100 nm with no change during more than 20 months' storage either at 4 °C or at room temperature. Franz diffusion cells studies showed that almost 4% of the applied formulations penetrated across the skin and the highest skin retention (73.92%) observed with Lip-AmB 0.4%. The median effective doses (ED50), the doses of AmB required to kill 50% of L. major amastigotes were 0.151, 0.151, and 0.0856 (µg/mL) in Lip-AmB 0.1, 0.2, 0.4%, respectively. Lip-AmB 0.4% caused 80% reduction in fluorescence intensity of GFP+ L. tropica infected macrophages at 5 µg/mL of AmB concentration. Topical Lip-AmB was applied twice a day for 4 weeks to the skin of BALB/c mice to treat lesions caused by L. major. Results showed the superiority of Lip-AmB 0.4% compared to Lip-AmB 0.2 and 0.1%. The parasite was completely cleared from the skin site of infection and spleens at week 8 and 12 post-infection in mice treated with Lip-AmB 0.4%. The results suggest that topical Lip-AmB 0.4% may be a useful tool in the treatment of CL and merits further investigation.

The molecular mechanisms of curcumin's inhibitory effects on cancer stem cells.

Curcumin is a dietary polyphenol and a bioactive phytochemical that possesses anti-inflammatory, antioxidant, anticancer, and chemopreventive properties, which make it capable of affecting multiple sites along the stem cell pathways to induce apoptosis in these cells. Curcumin's function is through suppression of cytokine release, especially the secretion of interleukins. Some of the predominant activities of stem cells include regeneration of identical cells and the ability to maintain the proliferation and multipotentiality. However, these cells could be stimulated to differentiate into specific cell types, leading to the development of tumors. Cancer stem cells (CSC) are capable of sustaining tumor formation and differentiation, and are normally characterized by self-renewal mechanisms. Furthermore, these cells might be responsible for tumor relapse and resistance to therapy. Several studies have focused on the mechanisms of curcumin action in manipulating transcription factors, signaling pathways, CSC markers, microRNAs related to CSCs functions and apoptosis induction in various human cancer cells. In the present review, we aimed to summarize the reported molecular mechanisms of curcumin's effects on CSCs.

Therapeutic Efficacy of Cisplatin Thermosensitive Liposomes upon Mild Hyperthermia in C26 Tumor Bearing BALB/c Mice.

This study reports on the activity of thermosensitive liposomes (TSLs) incorporating different HSPC ratios in DPPC/MSPC/PEG2000-DSPE matrix (90/10/4) plus mild hyperthermia (HT) (42 °C). TSLs were loaded with a poorly membrane permeable anticancer drug, cisplatin, through the passive equilibration method. The addition of HSPC to the corresponding DPPC lipid matrix increased the transition temperature. In vitro data demonstrated >90% cisplatin leakage from nanosized DPPC 90-lyso-TSL (LTSL) within 10 min at 42 °C, while other TSLs bearing HSPC showed greater stability. The plasma kinetics of cisplatin demonstrated higher cisplatin leakage from DPPC 90-LTSL in the first 4 h (from 17.4 to 0.4 µg/mL) compared to other formulations. Indeed, increasing HSPC fraction in liposome bilayers significantly improved drug retention in blood. Though DPPC 90-LTSL plus one-step HT was expected to provide a unique drug release, the premature drug leakage as well as the likely wash-back of a great portion of drug into the blood circulation resulted in reduced survival. On the other hand, stabilized DPPC 30/HSPC 60/MSPC 10/PEG2000-DSPE 4 liposomes plus two-step HT greatly enhanced the survival of animals. In particular, the improved delivery of cisplatin through stabilized DPPC 30/HSPC 60/MSPC 10/PEG2000-DSPE 4 liposomes in two-step mild HT enhanced antitumor efficacy compared to other formulations. Thus, prolonged exposure of cancer cells to cisplatin through stabilized liposomes would be an efficient approach in improving the survival of animals.

Targeting, bio distributive and tumor growth inhibiting characterization of anti-HER2 affibody coupling to liposomal doxorubicin using BALB/c mice bearing TUBO tumors.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-30% of breast cancer tumors. In the current investigation, we exploited such a feature and utilized an anti-HER2 affibody (ZHER2:477) in combination with a pegylated liposomal doxorubicin (PLD) for concurrent passive and active targeting of HER2 overexpressing TUBO tumor, using BALB/c mice. It was determined that the affibody coupled liposomes (affisomes) was capable of increasing doxorubicin (Dox) delivery to HER2+ cells (SK-BR-3 and TUBO cells), while transferring drug similarly as low as naïve PLD to HER2- MDA-MB-231 cells. This also resulted in selectively enhance cytotoxicity. The veracity of targeting was further assessed utilizing DiD lipophilic tracer model liposomes via competition assay. An approximated 10 ligand/liposome integration caused Dox delivery at 50% of maximal delivery capacity (Kd). Such integration did not alter Dox release in vitro, while it affected the serum clearance profile. Affibody integration to PLD increased drug concentration in tumor and led to significantly further augmentation of drug in liver and spleen compared to those of PLD. Overall, such differences led to prolonging the mice life spans as compared to PLD.