Reversible hydrophobic ion-paring complex strategy to minimize acylation of octreotide during long-term delivery from PLGA microparticles.

Acylation of peptide has been reported for a number of peptides and proteins during release from polymers comprising of lactide and glycolide. We hypothesize that reversible hydrophobic ion-pairing (HIP) complex may minimize octreotide acylation during release. Sodium dodecyl sulfate (SDS), dextran sulfate A (DSA, Mw 9-20 kDa) and dextran sulfate B (DSB, Mw 36-50 kDa) were selected as ion-pairing agents to prepare reversible HIP complex with octreotide.

Novel dexamethasone-loaded nanomicelles for the intermediate and posterior segment uveitis.

Development and characterization of dexamethasone (DEX)-encapsulated polymeric nanomicelles have been reported. A low molecular weight di-block copolymer was synthesized and characterized for its structure, molecular weights, critical micelle concentration (CMC), and cytotoxicity in ocular cells. In order to delineate the effects of drug-polymer interactions on drug solubilization in micelle core, a response surface methodology was generated with the help of SAS 9.

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir.

Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV.

In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management.

Retinoblastoma (RB) is a common malignant intraocular tumor primarily affecting children. Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in treatment of RB. Ocular cells have shown good tolerability against moxifloxacin (MFX).

Monocarboxylate transporter mediated uptake of moxifloxacin on human retinal pigmented epithelium cells.

Objectives: This work was aim to determine in vitro interaction of moxifloxacin with monocarboxylate transporter (MCT) using a human retinal pigment epithelium cells (ARPE-19).

Methods: In vitro moxifloxacin uptakes were performed at 37°C across ARPE-19 cells. Concentration-dependent uptake of moxifloxacin was performed to delineate moxifloxacin kinetics with MCT.

Microvascular complications and diabetic retinopathy: recent advances and future implications.

Retinal microvascular alterations have been observed during diabetic retinopathy (DR) due to the retinal susceptibility towards subtle pathological alterations. Therefore, retinal microvascular pathology is essential to understand the nature of retinal degenerations during DR. In this review, the role of retinal microvasculature complications during progression of DR, along with recent efforts to normalize such alterations for better therapeutic outcome, will be underlined.

Functional characterization and molecular expression of large neutral amino acid transporter (LAT1) in human prostate cancer cells.

The primary objective of this study is to functionally characterize and provide molecular evidence of large neutral amino acid transporter (LAT1) in human derived prostate cancer cells (PC-3). We carried out the uptake of [3H]-tyrosine to assess the functional activity of LAT1. Reverse transcription-polymerase chain reaction (RT-PCR) analysis is carried out to confirm the molecular expression of LAT1.

Design and evaluation of a novel nanoparticulate-based formulation encapsulating a HIP complex of lysozyme.

Formulation development of protein therapeutics using polymeric nanoparticles has found very little success in recent years. Major formulation challenges include rapid denaturation, susceptibility to lose bioactivity in presence of organic solvents and poor encapsulation in polymeric matrix. In the present study, we have prepared hydrophobic ion pairing (HIP) complex of lysozyme, a model protein, using dextran sulfate (DS) as a complexing polymer.

Mitochondrial localization of P-glycoprotein and peptide transporters in corneal epithelial cells--novel strategies for intracellular drug targeting.

This study was designed to investigate functional localization of both efflux (P-glycoprotein, P-gp) and influx (peptide) transporters in the mitochondrial membrane of cultured rabbit primary corneal epithelial cells (rPCECs). Isolation and purification of mitochondria was performed by optimized cell fractionation method. Mitochondrial integrity was measured by JC-1 uptake experiment.

Ocular toxicity from systemically administered xenobiotics.

Introduction: The eye is considered as the most privileged organ because of the blood-ocular barrier that acts as a barrier to systemically administered xenobiotics. However, there has been a significant increase in the number of reports on systemic drug-induced ocular complications. If such complications are left untreated, then it may cause permanent damage to vision.

Prodrug strategies in ocular drug delivery.

Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption.

Transporter-targeted lipid prodrugs of cyclic cidofovir: a potential approach for the treatment of cytomegalovirus retinitis.

Cidofovir (CDF) and its cyclic analogue (cCDF) have shown potential in vitro and in vivo antiviral activity against cytomegalovirus (CMV) retinitis. However, hydrophilic nature of CDF may affect cell permeation across lipophilic epithelium and thus limit its effectiveness in the treatment of CMV retinitis. In the present study, we have tested a novel hypothesis, which involves chemical derivatization of cCDF into lipophilic transporter-targeted prodrug [via conjugation with different carbon chain length of lipid raft and targeting moiety (biotin) for sodium-dependent multivitamin transporter (SMVT)].

Recent overview of ocular patents.

Ocular drug therapy has always been considered as a major challenge in the field of drug delivery. The presence of blood ocular barriers and efflux pumps has imposed a great concern as well. Various vision threatening disorders require a long term therapy of drug molecules, especially for the diseases that affect the posterior segment.

Mitochondrial dysfunction in retinal diseases.

The mitochondrion is a vital intracellular organelle for retinal cell function and survival. There is growing confirmation to support an association between mitochondrial dysfunction and a number of retinal degenerations. Investigations have also unveiled mitochondrial genomic instability as one of the contributing factors for age-related retinal pathophysiology.

Effect of emergence of fluoroquinolone resistance on intrinsic expression of P-glycoprotein phenotype in corneal epithelial cells.

Purpose: Multidrug resistance (MDR) represents a major obstacle to the success of antimicrobial fluoroquinolone (FQ) therapy. MDR-associated efflux protein pumps antimicrobial agents out of the corneal cells, leading to suboptimal eradication of microbes. This article examines whether long-term FQ (levofloxacin, ofloxacin, and gatifloxacin) therapy can modify the MDR phenotype (P-glycoprotein [P-gp]) on corneal epithelial cells (Statens Seruminstitut Rabbit Cornea [SIRC]).

Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis.

Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer, and activated CT-CTR autocrine axis plays a pivotal role in tumorigenicity and metastatic potential of multiple prostate cancer cell lines. Recent studies suggest that CT promotes prostate cancer metastasis by reducing cell-cell adhesion through the disassembly of tight and adherens junctions and activation of beta-catenin signaling. We attempted to identify a class of molecules that enhances cell-cell adhesion of prostate cells and reverses the disruptive actions of CT on tight and adherens junctions.

Cadherin switching and activation of beta-catenin signaling underlie proinvasive actions of calcitonin-calcitonin receptor axis in prostate cancer.

Calcitonin, a neuroendocrine peptide, and its receptor are localized in the basal epithelium of benign prostate but in the secretory epithelium of malignant prostates. The abundance of calcitonin and calcitonin receptor mRNA displays positive correlation with the Gleason grade of primary prostate cancers. Moreover, calcitonin increases tumorigenicity and invasiveness of multiple prostate cancer cell lines by cyclic AMP-dependent protein kinase-mediated actions.