Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control.

Insulin regulates blood glucose levels, and is the mainstay for the treatment of type-1 diabetes and type-2 when other drugs provide inadequate control. Therefore, effective oral Insulin delivery would be a significant advance in drug delivery. Herein, we report the use of the modified cell penetrating peptide (CPP) platform, Glycosaminoglycan-(GAG)-binding-enhanced-transduction (GET), as an efficacious transepithelial delivery vector in vitro and to mediate oral Insulin activity in diabetic animals. Insulin can be conjugated with GET via electrostatic interaction to form nanocomplexes (Insulin GET-NCs). These NCs (size and charge; 140 nm, +27.10 mV) greatly enhanced Insulin transport in differentiated in vitro intestinal epithelium models (Caco2 assays; >22-fold increased translocation) with progressive and significant apical and basal release of up-taken Insulin. Delivery resulted in intracellular accumulation of NCs, enabling cells to act as depots for subsequent sustained release without affecting viability and barrier integrity. Importantly Insulin GET-NCs have enhanced proteolytic stability, and retained significant Insulin biological activity (exploiting Insulin-responsive reporter assays). Our study culminates in demonstrating oral delivery of Insulin GET-NCs which can control elevated blood-glucose levels in streptozotocin (STZ)-induced diabetic mice over several days with serial dosing. As GET promotes Insulin absorption, transcytosis and intracellular release, along with in vivo function, our simplistic complexation platform could allow effective bioavailability of other oral peptide therapeutics and help transform the treatment of diabetes.

Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies.

Oral delivery of insulin and other anti-diabetic peptides is inhibited by low intestinal absorption caused by the poor permeability across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules by electrostatic or covalent conjugation on in conjunction with nanotechnology. Endogenous cellular uptake mechanisms present in the intestine can be exploited by engineering peptide conjugates that transcytose; entering cells by endocytosis and leaving by exocytosis. Efficiently delivering hydrophilic and sensitive peptide drugs to safely transverse the digestive barrier with no effect on gut physiology using remains a key driver for formulation research. Here we review the use of CPP and transcytosis peptide approaches, their modification and use in delivering anti-diabetic peptides (with the primary example of Insulin and engineered homologues) by direct oral administration to treat diabetes and associated metabolic disorders.

Alginate-polyvinyl alcohol based interpenetrating polymer network for prolonged drug therapy, Optimization and in-vitro characterization.

A new natural and synthetic polymeric blend to form interpenetrating polymer network (IPN) hydrogels was synthesized utilizing sodium alginate and PVA as polymers by free radical polymerization employing 2-Acylamido-2-methylpropane-sulfonic acid as monomer (AMPS) and tramadol HCl as model drug through 32 level full factorial design to evaluate the impact of selected independent factors i.e. polymer (sodium alginate) and monomer (AMPS) contents on swelling index at 18th hour, percent drug release at 18th hour, time required for 80% drug release and drug entrapment efficiency as dependent variables. FTIR, SEM, sol-gel analysis, equilibrium swelling studies and in-vitro release kinetics were performedfor in-vitro characterization of formulated IPN hydrogels. In-vitro studies carried out at pH 1.2 and pH 7.4 revealed pH independent swelling and drug release from polymeric IPN, providing controlled drug release for an extended period of time with improved entrapment efficiency, thereby concluding that this polymeric blend may be a promising system for the prolonged drug delivery.

Evaluation of Hormone Receptor Status (ER/PR/HER2-neu) in Breast Cancer in Pakistan.

OBJECTIVE: To evaluate the biological markers that are commonly assessed in breast cancer to estimate a patient's response to endocrine therapy and their prognosis for better clinical outcomes. METHODS: The retrospective study was conducted at Bahawalpur Institute of Nuclear Oncology and comprised record of early breast cancer patients who gave positive diagnostic tests for hormone receptors status i.e. immunohistochemical test and were treated during 2007-2013. Data of oestrogen, progesterone and human epidermal growth factor receptor 2 expression status was analysed. SPSS 12 was used for statistical analysis. RESULTS: Overall record of 345 patients was studied of whom 149(43%) were identified to have positive hormone receptor status.. The age of the patients ranged from 24 to 86 years with 97(65%) in 25-50 years, 46(30.8%) 51-75 years and 6(4.08%)in 76-100 years. Besides, 76(51%) patients had carcinoma of right breast; 86(58%) were diagnosed as Stage III, 55(37%) Stage II and 8(5.3%) Stage IV. Those diagnosed with oestrogen receptor (positive status) were 16(10.7%), human epidermal growth factor receptor 2 over-expression 13(8.7%), oestrogen/progesterone hormone receptor positivity (or luminal A) 76(51%) and 35(23.4%) patients were positive for all the three receptors. CONCLUSIONS: About half of the patients were diagnosed with a positive hormone status and it was observed that in most of the cases disease was metastasised to distant organs.