Studies in molecular modeling, in-vitro CDK2 inhibition and antimetastatic activity of some synthetic flavones.

Naturally occurring flavonoids have been shown to possess anticancer activity. We have previously shown that certain synthetic flavonoids also exert significant antiproliferative potential in MOLT-4, MCF-7, and HepG2 cell lines. To this end, we evaluated eight synthetic flavones for their CDK2 binding by molecular docking.

Evaluation of anti-metastatic potential of Cisplatin polymeric nanocarriers on B16F10 melanoma cells.

Nanoparticles are being increasingly used in the field of cancer treatment due to their unique properties and advantages. The aim of the present research work was to prepare and characterize a polymeric albumin nanosystem for Cisplatin and evaluate its in-vitro efficacy against B16F10 melanoma. The developed nanoparticles were almost spherical in shape with a particle size in the range of 150-300 nm, low polydispersity values and about 80% drug entrapment efficiency.

Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route.

Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB).

Endogenous galectin-3 expression levels modulate immune responses in galectin-3 transgenic mice.

Galectin-3 (Gal-3), a β-galactoside-binding mammalian lectin, is involved in cancer progression and metastasis. However, there is an unmet need to identify the underlying mechanisms of cancer metastasis mediated by endogenous host galectin-3. Galectin-3 is also known to be an important regulator of immune responses.

LeciPlex, invasomes, and liposomes: A skin penetration study.

The present study compares three vesicular systems, cationic LeciPlex, invasomes, and conventional liposomes for their ability to deliver drugs deep into the skin. Skin penetration ability of the three vesicular systems was studied for two drugs namely idebenone (antioxidant/anticancer) and azelaic acid (antiacne). All systems showed sizes in nanometer range with small polydispersity indices.

Role of tumor cell surface lysosome-associated membrane protein-1 (LAMP1) and its associated carbohydrates in lung metastasis.

Purpose: Expression of lysosome-associated membrane protein-1 (LAMP1) on the surface correlates with metastatic potential of B16 melanoma cells. Downregulation of their expression in high metastatic (B16F10) cells reduced their surface expression and metastatic potential. Present investigations explore if overexpression of LAMP1 on the surface of low metastatic (B16F1) cells augment their metastatic ability, and if so, how?

Methods: B16F1 cells were transduced with lentiviral vector carrying mutant-LAMP1 (Y386A) (mutLAMP1).

Docetaxel in cationic lipid nanocapsules for enhanced in vivo activity.

The usefulness of Docetaxel (DT) as an anti-cancer agent is limited to parenteral route owing to its very poor oral bioavailability. Thus, to improve its oral efficacy, DT was loaded in novel cationic lipid nanocapsules (DT CLNC). The DT CLNC possessed size of 130-150 nm, zeta potential of +72mV, adequate DT loading and over 95% encapsulation efficiency.

Liposomes for targeting hepatocellular carcinoma: use of conjugated arabinogalactan as targeting ligand.

Present study investigates the potential of chemically modified (Shah et al., 2013) palmitoylated arabinogalactan (PAG) in guiding liposomal delivery system and targeting asialoglycoprotein receptors (ASGPR) which are expressed in hepatocellular carcinoma (HCC). PAG was incorporated in liposomes during preparation and doxorubicin hydrochloride was actively loaded in preformed liposomes with and without PAG.

Apoptosis induction and anti-cancer activity of LeciPlex formulations.

Purpose: Cationic agents have been reported to possess anti-neoplastic properties against various cancer cell types. However, their complexes with lipids appear to interact differently with different cancer cells. The purpose of this study was to (i) design and generate novel cationic lecithin nanoparticles, (ii) assess and understand the mechanism underlying their putative cytotoxicity and (iii) test their effect on cell cycle progression in various cancer-derived cell lines.

Surface-coated PLA nanoparticles loaded with temozolomide for improved brain deposition and potential treatment of gliomas: development, characterization and in vivo studies.

Hydrophobicity of PLA nanoparticles makes them a good substrate for macrophageal and reticulo-endothelial system uptake. Long-circulating properties can be imparted to these particles by coating them with hydrophilic stabilizers. Surface-modified PLA nanoparticles loaded with anti-cancer agent temozolomide were fabricated by solvent evaporation method and coated with surface modifiers.

Galectin-3 expressed on different lung compartments promotes organ specific metastasis by facilitating arrest, extravasation and organ colonization via high affinity ligands on melanoma cells.

Interactions between molecules on the surface of tumor cells and those on the target organ endothelium play an important role in their arrest in an organ. Galectin-3 on the lung endothelium and high affinity ligands poly-N-acetyllactosamine (polyLacNAc) on N-oligosaccharides on melanoma cells facilitate such interactions. However, to extravasate and colonize an organ the cells must stabilize these interactions by spreading to retract endothelium, degrade exposed basement membrane (BM) and move into parenchyma and proliferate.

Regulation of melanoma metastasis to lungs by cell surface Lysosome Associated Membrane Protein-1 (LAMP1) via galectin-3.

Lysosome Associated Membrane Protein-1 (LAMP1), which lines the lysosomes, is often found to be expressed on surface of metastatic cells. We previously demonstrated that its surface expression on B16 melanoma variants correlates with metastatic potential. To establish the role of cell surface LAMP1 in metastasis and to understand the possible mechanism by which it facilitates lung colonization, LAMP1 was downregulated in high metastatic B16F10 cells using shRNAs cloned in a doxycycline inducible vector.

Anti-neuropilin 1 antibody Fab' fragment conjugated liposomal docetaxel for active targeting of tumours.

Neuropilin-1, a transmembrane receptor entailed in wide range of human tumour cell lines and diverse neoplasms, mediates the effects of VEGF and Semaphorins during the processes of cellular proliferation, survival and migration. In view of this, we had developed and evaluated in vitro and in vivo efficacy of anti-neuropilin-1 immunoliposomes against neuropilin-1 receptor expressing tumours. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method.

Tamoxifen guided liposomes for targeting encapsulated anticancer agent to estrogen receptor positive breast cancer cells: in vitro and in vivo evaluation.

Tamoxifen (TMX), an estrogen receptor (ER) antagonist, incorporated at surface of liposomes loaded with Doxorubicin (DOX), was hypothesized to serve as ligand for targeting overexpressed ERs on surface and cytosol of breast cancer cells, in addition to its synergism with DOX in killing MCF-7 cells. The TMX-DOX liposomes demonstrated mean size of 188.8±2.

Etoposide loaded solid lipid nanoparticles for curtailing B16F10 melanoma colonization in lung.

Poor solubility of etoposide and associated poor bioavailability of the drug was circumvented by developing solid lipid nanocarrier system. The objective of the research work was to prepare etoposide loaded solid lipid nanoparticles (SLN) for improved efficacy and therapy of metastasized cancers. Entrapment of drug into nanoparticulate system modifies the pharmacokinetic and biodistribution profile of the drug with improved therapeutic efficacy.

Unraveling the cytotoxic potential of Temozolomide loaded into PLGA nanoparticles.

Background: Nanotechnology has received great attention since a decade for the treatment of different varieties of cancer. However, there is a limited data available on the cytotoxic potential of Temozolomide (TMZ) formulations. In the current research work, an attempt has been made to understand the anti-metastatic effect of the drug after loading into PLGA nanoparticles against C6 glioma cells.

Delineating the anti-metastatic potential of pentoxifylline in combination with liposomal doxorubicin against breast cancer cells.

Breast cancer remains the second most prevalent cancer worldwide. Several anticancer drugs are being currently used in the treatment of breast cancer. However, owing to high cytotoxicity, induced resistance and cost ineffectiveness, there is an urgent need to develop newer therapeutic regimens that limit the current problems.

Pentoxifylline regulates the cellular adhesion and its allied receptors to extracellular matrix components in breast cancer cells.

Pentoxifylline (PTX) is a methylxanthine derivative that improves blood flow by decreasing its viscosity. Being an inhibitor of platelet aggregation, it can thus reduce the adhesiveness of cancer cells prolonging their circulation time. This delay in forming secondary tumours makes them more prone to immunological surveillance.

Role of STAT3 in cancer metastasis and translational advances.

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated.

Lipid colloidal carriers for improvement of anticancer activity of orally delivered quercetin: formulation, characterization and establishing in vitro-in vivo advantage.

Novel lipid nanocarriers, GeluPearl (GP) comprising of Precirol ATO 5 lipid nanoparticles with (GPNLC) or without oil (GPSLN), loaded with Quercetin (QR), were successfully fabricated to improve therapeutic efficacy. QR loaded GP nanoparticles were optimized to yield adequate colloidal stability, mean particle size in range of 350-380 nm and entrapment efficiency of more than 90%. GPSLN and GPNLC were characterized for morphological evaluation by virtue of cryo-TEM, surface charge, protection offered to QR against alkali mediated degradation and fluorescence studies to evaluate QR-lipid interaction.

Curbing the focal adhesion kinase and its associated signaling events by pentoxifylline in MDA-MB-231 human breast cancer cells.

Pentoxifylline (PTX) is a methylxanthine derivative currently being used in the treatment of peripheral vascular diseases. Recently, we had evaluated its action in human MDA-MB-231 breast cancer cells. PTX exhibited anti-metastatic activity by affecting key processes such as proliferation, adhesion, migration, invasion and apoptosis.

Is an alternative drug delivery system needed for docetaxel? The role of controlling epimerization in formulations and beyond.

Purpose: The presence of 7-epidocetaxel in docetaxel injection and in vivo epimerisation has been reported to be the cause for development of tumor resistance to chemotherapy including docetaxel by inducing tumor cell protein cytochrome P450 1B1. The objective of this study was to determine systemic toxicity of Taxotere® containing 10% 7-epidocetaxel and to develop PEGylated liposomal injection that could resist epimerization in vivo. Another need for PEGylated liposomal delivery of docetaxel is to avoid reported hypersensitivity reactions of marketed products like Taxotere® and Duopafei® containing high concentration of tween-80.

Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway.

Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to have anti-metastatic or anti-angiogenic activity against many human cancers. However, the underlying mechanisms are unknown. In this study, we report that, PTX at sub-toxic doses can inhibit melanoma tumor growth and angiogenesis by targeting the STAT3 signaling pathway.

Type II phosphatidylinositol 4-kinase β is an integral signaling component of early T cell activation mechanisms.

The early signaling events in T cell activation through CD3 receptor include a rapid change in intra cellular free calcium concentration and reorganization of actin cytoskeleton. Phosphatidylinositol 4-kinases (PtdIns 4-kinases) are implicated as key components in these early signaling events. The role of type II PtdIns 4-kinase β in CD3 receptor signaling was investigated with the help of short hairpin RNA sequences.

Studies on stabilization mechanism and stealth effect of poloxamer 188 onto PLGA nanoparticles.

In nanoparticulate engineering for drug delivery systems, poloxamers tri block copolymers are employed as adsorbing molecules to modify the aggregation state and impart stability to products. The aim was to prepare nanoparticles using poloxamer188 as stabiliser and investigate the mechanism of stabilisation of the prepared particles. Nanoparticles were prepared by solvent diffusion method with poloxamer 188 as stabiliser.