Micelles in Cancer Therapy: An Update on Preclinical and Clinical Status

Background: In the recent years, Micelles represent a promising carrier for the treatment and diagnosis of cancer. Architecturally, micelles are self-assembled nanosized colloidal aggregates prepared from amphiphilic surfactant with a hydrophobic core and hydrophilic shell. Such composition making them a potential carrier for delivery of hydrophobic anticancer drugs with in their core. Description: Micelles have received increasing interest as an enhanced permeability and retention (EPR) targeted drug delivery systems for cancer treatment. Micelles can be modified to contribute various attractive properties for instance active targeting, stimuli-responsiveness. They have also proven their ability in drug targeting to tumor tissue, enhanced drug accumulation, drug stabilization, tissue penetration, prolong circulation, in vivo biocompatibility, biodegradability and, reduced side effects. Micelles have displayed vital role in multidrug delivery for cancer therapy. Results and Discussion : The aim of the present review is to provide an overview on the status of micellar nanoformulations for anticancer agents, including their pre-clinical and clinical researches. Emphasis is placed on presenting the newer strategies to enhance the therapeutic efficacy of anticancer drug at target site. The type of co-polymers used and methods for the preparation of micelles are also highlighted in the paper.

Characterization and Evaluation of Ternary Complexes of Ascorbic Acid with γ-Cyclodextrin and Poly(vinyl Alcohol)

Ascorbic acid (AA) is a general antioxidant used in aqueous pharmaceutical formulations. However, in aqueous solutions, AA is unstable and easily oxidized when exposed to air, light and/or heat. Cyclodextrins are well known for their ability to form inclusion complexes with various compounds to improve their solubility and stability. Previous studies demonstrate that cyclodextrins preserve the antioxidant capacity of AA but data for γ-cyclodextrin (γCD) have not been reported. Poly(vinyl alcohol) (PVA) is a hydrophilic polymer widely used as a drug matrix in various pharmaceutical fields, but its application for drug stabilization is limited. This study aimed to investigate the protective ability of γCD on AA through the formation of ternary complexes with PVA. Binary (i.e., AA/γCD, AA/PVA and γCD/PVA) and ternary (i.e., AA/γCD/PVA) complexes were first confirmed. It was reported that those complexes were formed through interactions between the heterocyclic ring of AA, hydroxyl group of PVA and hydrophobic cavity of γCD. The hydrodynamic diameter of complexes was then studied. It was found that the diameter of γCD/PVA complexes increased with respect to the concentration of γCD. Higher γCD concentrations also resulted in increasing hydrodynamic diameters of the ternary complex. The presence of AA in ternary complexes interfered with the aggregation tendency of γCD/PVA binary complexes. Furthermore, the antioxidant capacity of AA in binary and ternary complexes was investigated. It was found that the presence of γCD preserved the antioxidant activity of AA, whereas PVA showed a contrasting effect. The influence of γCD and PVA concentration on antioxidant capacity was then studied through central composite design (CCD). Even though the concentration of γCD significantly affected the inhibition efficiency of the ternary complex, the insignificant influence of PVA could not be ignored. A promising protective ternary complex should consist of an optimized concentration of PVA and a high concentration of γCD.

Development of Novel Silica-Based Formulation of α-Lipoic Acid: Evaluation of Photo and Thermal Stability of the Encapsulated Drug

Powerful antioxidant α-lipoic acid (LA) is easily degraded under light and heating. This creates difficulties in its manufacture, storage and reduces efficiency and safety of the drug. The purpose of this work was to synthesize novel silica-based composites of LA and evaluate their ability to increase photo and thermal stability of the drug. It was assumed that the drug stabilization can be achieved due to LA-silica interactions. Therefore, the composites of LA with unmodified and organomodified silica matrixes were synthesized by sol-gel method at the synthesis pH below or above the pKa of the drug. The effects of silica matrix modification and the synthesis pH on the LA-silica interactions and kinetics of photo and thermal degradation of LA in the composites were studied. The nature of the interactions was revealed by FTIR spectroscopy. It was found that the rate of thermal degradation of the drug in the composites was significantly lower compared to free LA and mainly determined by the LA-silica interactions. However, photodegradation of LA in the composites under UV irradiation was either close to that for free drug or significantly more rapid. It was shown that kinetics of photodegradation was independent of the interactions and likely determined by physical properties of surface of the composite particles (porosity and reflectivity). The most promising composites for further development of novel silica-based formulations were identified.

Selective eradication of human non-small cell lung cancer cells using aptamer-decorated nanoparticles harboring a cytotoxic drug cargo

Targeted cancer therapy is currently the leading modality to enhance treatment selectivity and efficacy, as well as to minimize untoward toxicity to healthy tissues. Herein, we devised and studied nanoparticles (NPs) composed of the biocompatible block-copolymer PEG-PCL entrapping the hydrophobic chemotherapeutic drug paclitaxel (PTX), which are targeted to human non-small cell lung cancer (NSCLC) cells. To achieve selective NSCLC targeting, these NPs were decorated with single-stranded oligonucleotide-based S15 aptamers (S15-APTs), which we have recently shown to serve as efficient tumor cell targeting ligands. Prepared without using surfactants, these 15 nm PEG-PCL/PTX NPs entered NSCLC cells via clathrin-mediated endocytosis. These NPs demonstrated efficient encapsulation of PTX, high selectivity to- and potent eradication of human A549 NSCLC cells, with a remarkable half maximal inhibitory concentration (IC50) of 0.03 μM PTX. In contrast, very high IC50 values of 1.7, 4.2, 43, 87, and 980 µM PTX were obtained towards normal human bronchial epithelial BEAS2B, cervical carcinoma HeLa, colon adenocarcinoma CaCo-2, neonatal foreskin fibroblast FSE, and human embryonic kidney HEK-293 cells, respectively. These results demonstrate 2–5 orders of magnitude difference in the selective cytotoxicity towards NSCLCs, reflecting a potentially outstanding therapeutic window. Moreover, the dual utility of aptamer-decorated NPs for both drug stabilization and selective tumor targeting was studied by increasing APT concentrations during NP “decoration”. The optimal aptamer density on the surface of NPs for selective targeting, for high fluorescence diagnostic signal and for maintaining small particle size to enable endocytosis, was achieved by using 30 nM APTs during NP decoration. Collectively, our findings suggest that these APT-decorated NPs hold great preclinical promise in selective targeting and eradication of human NSCLC cells without harming normal tissues.

Hydroxyapatite/PLA Biocomposite Thin Films for Slow Drug Delivery of Antibiotics for the Treatment of Bone and Implant-Related Infections

Drug delivery systems were developed from coralline hydroxyapatite (HAp) and biodegradable polylactic acid (PLA). Gentamicin (GM) was loaded in either directly to PLA (PLAGM) or in HAp microspheres. Drug loaded HAp was used to make thin film composites (PLAHApGM). Dissolution studies were carried out in phosphate buffered saline (PBS. The release profiles suggested that HAp particles improved drug stabilization and availability as well control the release rate. The release also displays a steady state release. In vitro studies in human Adipose Derived Stem Cells (hADSCs) showed substantial quantities of cells adhering to hydroxyapatite containing composites. The results suggested that the systems could be tailored to release different clinical active substances for a wide range of biomedical applications.