No abstract

Cluster of differentiation-44 (CD44) is a ubiquitously present glycoprotein on the surface of mammalian cells that plays a significant role in a number of biological functions. Since the discovery that the receptor is over-expressed in a variety of solid tumors, such as pancreatic, breast and lung cancer, many studies have focused on methods for targeting CD44 in an attempt to improve drug delivery and discrimination between healthy and malignant tissue, while reducing residual toxicity and off-target accumulation. In this review, we describe CD44 receptor biology and its involvement in the different stages of tumor growth and metastasis, as well as methods currently used for targeting the receptor. Hyaluronic acid, the primary CD44 binding molecule, has proved a significant ally in developing nanocarriers that demonstrate preferential tumor accumulation and increased cell uptake. We outline a number of research approaches from the current literature that take advantage of hyaluronic acid's targeting ability and describe the possible advantages for each approach. The value of CD44 targeting can be easily appreciated from the number of different approaches that have reached clinical trials.

Despite the substantial recent progress made in extracellular vesicle (EV) research, our understanding of the functional and mechanistic biology of EVs and their relevance to specific pathophysiological states remains limited.Detailed characterization of the molecular composition of EVs and EV subpopulations remains a challenge.Alternative, similar, or identical experimental approaches may often lead to substantially different EV profiling results in different laboratories.Standard protocols for specimen procurement, collection, preprocessing, EV isolation, analytical characterization, and data analysis/interpretation need to be developed for specialized applications and analytical workflows, optimized, documented, cross-evaluated by several laboratories, and disseminated to further accelerate progress toward further understanding of EV biology and development of novel EV-based diagnostic and therapeutic approaches.

Novel optical imaging methods, such as Raman microspectroscopy, have been gaining recognition in their ability to obtain noninvasively the distribution of biochemical components of a sample. Raman spectroscopy in combination with optical microscopy provides a label-free method to assess and image cellular processes, without the use of extrinsic fluorescent dyes. The submicrometer resolution of the confocal Raman instrumentation allows us to image cellular organelles on the scale of conventional microscopy. We used the technique to monitor subcellular degradation patterns of two biodegradable nanocarrier systems-poly(epsilon-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA). Our results suggest that both drug-delivery systems eventually are incorporated into Golgi-associated vesicles of late endosomes. These processes were monitored via the decrease of the molecule-characteristic peaks of PCL and PLGA. As the catabolic pathways proceed, shifts and variations in peak intensities and intensity ratios in the rendered Raman spectra unequivocally delineate their degradation patterns.

BackgroundThe use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy.Methodology/Principal FindingsIn order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines.Conclusions/SignificanceLipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.