Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects.

The deregulation of the epidermal growth factor receptor (EGFR) has a significant role in the progression of tumors. Despite the development of a number of EGFR-targeting agents that can arrest tumor growth, their success in the clinic is limited in several tumor types, particularly in the highly malignant glioblastoma multiforme (GBM). In this study, we generated and characterized EGFR-specific nanobodies (ENb) and imageable and proapoptotic ENb immunoconjugates released from stem cells (SC) to ultimately develop a unique EGFR-targeted therapy for GBM. We show that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling resulting in reduced GBM growth and invasiveness in vitro and in vivo in both established and primary GBM cell lines. We also show that ENb primes GBM cells for proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, SC-delivered immunoconjugates of ENb and TRAIL target a wide spectrum of GBM cell types with varying degrees of TRAIL resistance and significantly reduce GBM growth and invasion in both established and primary invasive GBM in mice. This study demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.

Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors.

Only a subset of cancer patients inoculated with oncolytic herpes simplex virus (oHSV) type-1 has shown objective response in phase 1 and 2 clinical trials. This has raised speculations whether resistance of tumor cells to oHSV therapy may be a limiting factor. In this study, we have identified established and patient derived primary glioblastoma multiforme (GBM) stem cell lines (GSC) resistant to oHSV and also to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that has recently shown promise in preclinical and initial clinical studies. We created a recombinant oHSV bearing a secretable TRAIL (oHSV-TRAIL) and hypothesized that oHSV-TRAIL could be used as a cancer therapeutic to target a broad spectrum of resistant tumors in a mechanism-based manner. Using the identified resistant GBM lines, we show that oHSV-TRAIL downregulates extracellular signal-regulated protein kinase (ERK)-mitogen-activated protein kinase (MAPK) and upregulates c-Jun N-terminal kinase (JNK) and p38-MAPK signaling, which primes resistant GBM cells to apoptosis via activation of caspase-8, -9, and -3. We further show that oHSV-TRAIL inhibits tumor growth and invasiveness and increases survival of mice bearing resistant intracerebral tumors without affecting the normal tissues. This study sheds new light on the mechanism by which oHSV and TRAIL function in concert to overcome therapeutic-resistance, and provides an oncolytic virus based platform to target a broad spectrum of different cancer types.

Pre-filled syringe - a ready-to-use drug delivery system: a review.

INTRODUCTION: Fueled by a growing global expectation of the health and medical fields, billions of dollars/euros/pounds are invested every year in the research of new biological and chemical entities. However, little interest is seen in the development of novel drug delivery systems. One such system, pre-filled syringe (PFS), was invented decades ago but is still a rare mode of delivery in many therapeutic segments. AREAS COVERED: This review comprises properties and effects of extractables, leachables and discuss the characteristics of PFS technology; its composition, glass and polymer types, configuration of PFS, advantages over glass, technical and commercial applicability; its significance against patient, industry, quality, environment and cost; and its business potential. We discuss in brief about PFS used in various major and life-threatening disorders and future prospects. It provides showers of knowledge in the field of PFS drug delivery technology to the reader's, industrialist's and researcher's point of view. EXPERT OPINION: The PFS drug delivery system offers a wonderful panorama to lifesaving drugs that are currently only available in conventional vials and ampoules in the market. A novel approach of Form Fill Seal technology can be adopted for this particular ready-to-use dosage form also, which opens the new global doors for budding researchers in the field of pre-filled drug delivery system.

A world of low molecular weight heparins (LMWHs) enoxaparin as a promising moiety--a review.

Anti-coagulants are one of the most important categories in healthcare therapeutics. For healthcare professionals dealing in cases of in-vivo blood clotting problems. Heparin and low molecular weight heparins (LMWHs) would be the first choice of drugs. This review represents an overview of the LMWHs, their importance over heparin and enlightens the advancements. In addition to these, different methods used for preparation and purification are discuss in terms of production and synthesis. Worldwide availability in pre-filled syringe, market, manufacturers and suppliers drug interactions, adverse drug reactions, in-vitro study, freezing/thawing process and structural differences of LMWHs are also focused upon in this review.