TRAIL therapy and prospective developments for cancer treatment.

Tumor Necrosis Factor (TNF) Related Apoptosis-Inducing Ligand (TRAIL), an immune cytokine of TNF-family, has received much attention in late 1990s as a potential cancer therapeutics due to its selective ability to induce apoptosis in cancer cells. TRAIL binds to cell surface death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) and facilitates formation of death-inducing signaling complex (DISC), eventually activating the p53-independent apoptotic cascade. This unique mechanism makes the TRAIL a potential anticancer therapeutic especially for p53-mutated tumors.

Enabling Combinatorial siRNA Delivery against Apoptosis-Related Proteins with Linoleic Acid and α-Linoleic Acid Substituted Low Molecular Weight Polyethylenimines.

Purpose: Short interfering RNA (siRNA) therapy promises a new era in treatment of breast cancers but effective delivery systems are needed for clinical use. Since silencing complementary targets may offer improved efficacy, this study was undertaken to identify non-viral carriers for combinatorial siRNA delivery for more effective therapy.

Methods: A library of lipid-substituted polymers from low molecular weight polyethyleneimine (PEI), linoleic acid (LA) and α-linoleic acid (αLA) with amide or thioester linkages was prepared and investigated for delivering Mcl-1, survivin and STAT5A siRNAs in breast cancer cells.

A systematic comparison of lipopolymers for siRNA delivery to multiple breast cancer cell lines: In vitro studies.

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery.

Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy.

Synthetic siRNA technology has emerged as a promising approach for molecular therapy of cancer but, despite its potential for post-transcriptional gene silencing, there is an urgent need to develop efficient delivery systems particularly for difficult-to-transfect, anchorage-independent cells. In this study, we designed highly hydrophobic cationic lipopolymers by grafting cholesterol (Chol) onto low-molecular weight (0.6, 1.

Breathing New Life into TRAIL for Breast Cancer Therapy: Co-Delivery of pTRAIL and Complementary siRNAs Using Lipopolymers.

Preclinical studies showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of TRAIL protein, insufficient induction of apoptosis, and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary small interfering RNAs (siRNAs) (silencing [BCL2L12] and [SOD1]) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA.

siRNA Library Screening to Identify Complementary Therapeutic Pairs in Triple-Negative Breast Cancer Cells.

The existence of tightly integrated cross talk through multiple signaling and effector pathways has been appreciated in malignant cells. The realization of the plasticity of such networks is stimulating the development of combinational therapy to overcome the limitations of one-dimensional therapies. Synergistic pairs of siRNAs or siRNA and drug combinations are the new frontiers in identifying effective therapeutic combinations.

Silencing by siRNA: A Potent Approach to Sensitize Chronic Myeloid Leukemia Cells to Tyrosine Kinase Inhibitor Therapy.

Nonviral gene therapy with specific short interfering RNAs (siRNAs) against can be an alternative and/or supportive therapy of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs), given the often observed resistance to TKIs in clinical setting. In this study, we explored the feasibility of BCR-Abl siRNA therapy in CML K562 cells in vitro by employing a cationic polymer derived from cholesterol (Chol) grafted low-molecular weight polyethyleneimine (PEI). The first generation TKI imatinib upregulated the expression of in K562 cells as expected.

Novel targets for sensitizing breast cancer cells to TRAIL-induced apoptosis with siRNA delivery.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in variety of cancer cells without affecting most normal cells, which makes it a promising agent for cancer therapy. However, TRAIL therapy is clinically not effective due to resistance induction. To identify novel regulators of TRAIL that can aid in therapy, protein targets whose silencing sensitized breast cancer cells against TRAIL were screened with an siRNA library against 446 human apoptosis-related proteins in MDA-231 cells.

Nucleic acid combinations: A new frontier for cancer treatment.

The emerging molecular understanding of cancer cell behavior is leading to increasing possibilities to control unchecked cell growth and metastasis. On the other hand, development of multifunctional drug carriers at the 'nano'-scale is providing exciting new therapeutic strategies in clinical management of cancer beyond the conventional cytotoxic drugs. A new frontier in this regard is the combinational use of complementary agents based on nucleic acids to overcome the limitations of conventional therapy.

Small hydrophobe substitution on polyethylenimine for plasmid DNA delivery: Optimal substitution is critical for effective delivery.

Unlabelled: Cationic polymers have been turned into effective gene delivery agents by functionalizing with long-chain aliphatic lipids, but little information exists if small hydrophobic moieties can serve as effective substituents for this purpose. To explore this issue, we modified small molecular weight (1.2kDa) polyethylenimine (1.

Asialoglycoprotein Receptor-Mediated Gene Delivery to Hepatocytes Using Galactosylated Polymers.

Highly efficient, specific, and nontoxic gene delivery vector is required for gene therapy to the liver. Hepatocytes exclusively express asialoglycoprotein receptor (ASGPR), which can recognize and bind to galactose or N-acetylgalactosamine. Galactosylated polymers are therefore explored for targeted gene delivery to the liver.

Dual secured nano-melittin for the safe and effective eradication of cancer cells.

The clinical application of natural and synthetic amphipathic peptides (e.g., melittin) for cancer therapy is hindered by their notorious side effect, lysing red blood cells.

pH and redox dual responsive nanoparticle for nuclear targeted drug delivery.

To mimic the clinic dosing pattern, initially administering high loading dose and then low maintenance dose, we designed a novel poly(2-(pyridin-2-yldisulfanyl)ethyl acrylate) (PDS) based nanoparticle delivery system. Side chain functional PDS was synthesized by free radical polymerization. Polyethylene glycol and cyclo(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide was conjugated to PDS through thiol-disulfide exchange reaction to achieve RPDSG polymer.

Design of serum compatible tetrary complexes for gene delivery.

A novel gene delivery system, called PoSC, consisting of PEI, PSP, and HA is described. In contrast to the DNA/PEI/HA ternary system whose transfection efficiency decreases significantly with increasing serum concentration, PoSC exhibits a high transfection efficiency of about 51 and 87% for NIH3T3 and HCT116 cells, respectively, at 50% serum concentration. Furthermore, PoSC shows no cytotoxic effect at its working concentration.

High-performance liquid chromatography analysis of capsaicin content in 16 Capsicum fruits from Nepal.

Capsicum fruit, a popular spice as chili pepper, is an important ingredient of the formulations used in traditional medicines. Moreover, Capsicum fruit is listed as an official drug in several pharmacopoeias. Capsaicin, the most abundant component in Capsicum fruit, exhibits its therapeutic and adverse effects in a dose-dependent manner.