Importance of ABC Transporters in the Survival of Parasitic Nematodes and the Prospect for the Development of Novel Control Strategies.

ABC transporters, a family of ATP-dependent transmembrane proteins, are responsible for the active transport of a wide range of molecules across cell membranes, including drugs, toxins, and nutrients. Nematodes possess a great diversity of ABC transporters; however, only P-glycoproteins have been well-characterized compared to other classes. The ABC transport proteins have been implicated in developing resistance to various classes of anthelmintic drugs in parasitic nematodes; their role in plant and human parasitic nematodes still needs further investigation. Therefore, ABC transport proteins offer a potential opportunity to develop nematode control strategies. Multidrug resistance inhibitors are becoming more attractive for controlling nematodes due to their potential to increase drug efficacy in two ways: (i) by limiting drug efflux from nematodes, thereby increasing the amount of drug that reaches its target site, and (ii) by reducing drug excretion by host animals, thereby enhancing drug bioavailability. This article reviews the role of ABC transporters in the survival of parasitic nematodes, including the genes involved, their regulation and physiological roles, as well as recent developments in their characterization. It also discusses the association of ABC transporters with anthelmintic resistance and the possibility of targeting them with next-generation inhibitors or nutraceuticals (e.g., polyphenols) to control parasitic infections.

Measuring the oral bioavailability of protein hydrolysates derived from food sources: A critical review of current bioassays.

BACKGROUND: Food proteins are a source of hydrolysates with potentially useful biological attributes. Bioactive peptides from food-derived proteins are released from hydrolysates using exogenous industrial processes or endogenous intestinal enzymes. Current in vitro permeability assays have limitations in predicting the oral bioavailability (BA) of bioactive peptides in humans. There are also difficulties in relating the low blood levels of food-derived bioactive peptides detected in preclinical in vivo models to pharmacodynamic read-outs relevant for humans. SCOPE AND APPROACH: In this review, we describe in vitro assays of digestion, permeation, and metabolism as indirect predictors of the potential oral BA of hydrolysates and their constituent bioactive peptides. We discuss the relationship between industrial hydrolysis processes and the oral BA of hydrolysates and their peptide by-products. KEY FINDINGS: Hydrolysates are challenging for analytical detection methods due to capacity for enzymatic generation of peptides with novel sequences and also new modifications of these peptides during digestion. Mass spectrometry and peptidomics can improve the capacity to detect individual peptides released from complex hydrolysates in biological milieu.

Silica nanoparticles: A promising platform for enhanced oral delivery of macromolecules.

Oral ingestion remains as the most convenient route of administration for the application of pharmaceuticals since it is non-invasive and does not require trained personnel to administer the drugs. Despite significant progress in novel oral drug delivery platforms over the past few decades, the oral delivery of macromolecules (particularly for peptides and proteins) is one of the major challenges faced by the biopharmaceutical industry. This is even more important since a large number of biologic drugs have been available in the past decade which typically require intravenous administration. Recently, silica nanoparticles have emerged as multifunctional, biocompatible and biodegradable inorganic nanocarriers with enormous potential as an oral drug delivery platform for various therapeutics including macromolecules. Their unique structural composition facilitates the loading of large therapeutic payloads at desired loading capacities for a controlled and site-specific oral delivery. Here, we review first the physiological challenges for oral delivery of peptides and proteins. Next, we discuss silica-based functional materials for oral delivery of macromolecules and highlight their evolving role not only as an encapsulant but as a permeation enhancer as well. Lastly, we also discuss potential strategies for future translation of these novel materials to the clinic.

Encapsulation and Controlled Release of Resveratrol Within Functionalized Mesoporous Silica Nanoparticles for Prostate Cancer Therapy.

Resveratrol (RES) is a naturally existing polyphenol which exhibits anti-oxidant, anti-inflammatory, and anti-cancer properties. In recent years, RES has attracted attention for its synergistic effect with other anti-cancer drugs for the treatment of drug resistant cancers. However, RES faces the issues of poor pharmacokinetics, stability and low solubility which limits its clinical application. In present study, RES has been loaded onto uniformly sized (~60 nm) mesoporous silica nanoparticles (MSNs) to improve its in vitro anti-proliferative activity and sensitization of Docatexal in hypoxia induced drug resistance in prostate cancer. RES was efficiently encapsulated within phosphonate (negatively charged) and amine (positively charged) modified MSNs. The effect of surface functionalization was studied on the loading, in vitro release, anti-proliferative and cytotoxic potential of RES using prostate cancer cell line. At pH 7.4 both free and NH2-MSNs loaded RES showed burst release which was plateaued with almost 90% of drug released in first 12 h. On the other hand, PO3-MSNs showed significantly slower release kinetics with only 50% drug release in first 12 h at pH 7.4. At pH 5.5, however, both the PO3-MSNs and NH2-MSNs showed significant control over release (around 40% less release compared with free RES in 24 h). Phosphonate modified MSNs significantly enhanced the anti-proliferative potential of RES with an IC50 of 7.15 µM as compared to 14.86 µM of free RES whereas amine modified MSNs didn't affect proliferation with an IC50 value higher than free RES (20.45 µM). Furthermore, RES loaded onto PO3-MSNs showed robust and dose dependent sensitization of Docatexal in hypoxic cell environment which was comparable to pure RES solution. This study provides an example of applicability of MSNs loaded with polyphenols such as RES as next generation anticancer formulations for treating drug resistant cancers such as prostate cancer.

Efficient photoacoustic imaging using indocyanine green (ICG) loaded functionalized mesoporous silica nanoparticles.

Photoacoustic (PA) imaging is gaining momentum due to its greater depth of field, low background, and 3D imaging capabilities. However, traditional PA imaging agents (e.g. dyes, quantum dots, etc.) are usually unstable in plasma and bind to serum proteins, and thus cleared rapidly. Because of this, the nanoparticle encapsulation of PA imaging agents is becoming increasingly popular. Therefore, the rational design of carrier nanoparticles for this purpose is necessary for strong imaging signal intensity, high biosafety, and precise targeting. Herein, we systematically evaluate the influence of the chemical and physical surface functionalization of mesoporous silica nanoparticles (MSNs) on the photo-stability, loading, release, and photoacoustic (PA) signal strength of the FDA approved small molecule contrast agent, indocyanine green (ICG). Chemical functionalization involved the modification of MSNs with silanes having amine (NH2) or phosphonate (PO3) terminal groups, whereas physical modifications were performed by capping the ICG loaded MSNs with lipid bilayer (LB) or layer-by-layer (LBL) polyelectrolyte coatings. The NH2-MSNs display the highest ICG mass loading capacity (16.5 wt%) with a limited release of ICG (5%) in PBS over 48 h, while PO3-MSNs only loaded ICG around 3.5 wt%. The physically modified MSNs (i.e. LBMSNs and LBLMSNs) were vacuum loaded resulting in approximately 9 wt% loading and less than 10% ICG release in 48 h. Pure ICG was highly photo-unstable and showed 20% reduction in photoluminescence (PL) within 3 h of exposure to 800 nm, while the ICG loaded onto functionalized MSNs did not photo-degrade. Among the tested formulations, NH2-MSNs and LBLMSNs presented 4-fold in vitro PA signal intensity enhancement at a 200 µg mL-1 equivalent ICG dose. Similar to the in vitro PA imaging, NH2-MSNs and LBLMSNs performed the best when subcutaneously injected into mouse cadavers with 1.29- and 1.43-fold PA signal enhancement in comparison to the pure ICG, respectively.

Rationally Designed Dendritic Silica Nanoparticles for Oral Delivery of Exenatide.

Type 2 diabetes makes up approximately 85% of all diabetic cases and it is linked to approximately one-third of all hospitalisations. Newer therapies with long-acting biologics such as glucagon-like peptide-1 (GLP-1) analogues have been promising in managing the disease, but they cannot reverse the pathology of the disease. Additionally, their parenteral administration is often associated with high healthcare costs, risk of infections, and poor patient adherence associated with phobia of needles. Oral delivery of these compounds would significantly improve patient compliance; however, poor enzymatic stability and low permeability across the gastrointestinal tract makes this task challenging. In the present work, large pore dendritic silica nanoparticles (DSNPs) with a pore size of ~10 nm were prepared, functionalized, and optimized in order to achieve high peptide loading and improve intestinal permeation of exenatide, a GLP-1 analogue. Compared to the loading capacity of the most popular, Mobil Composition of Matter No. 41 (MCM-41) with small pores, DSNPs showed significantly high loading owing to their large and dendritic pore structure. Among the tested DSNPs, pristine and phosphonate-modified DSNPs (PDSNPs) displayed remarkable loading of 40 and 35% w/w, respectively. Furthermore, particles successfully coated with positively charged chitosan reduced the burst release of exenatide at both pH 1.2 and 6.8. Compared with free exenatide, both chitosan-coated and uncoated PDSNPs enhanced exenatide transport through the Caco-2 monolayer by 1.7 fold. Interestingly, when a triple co-culture model of intestinal permeation was used, chitosan-coated PDSNPs performed better compared to both PDSNPs and free exenatide, which corroborated our hypothesis behind using chitosan to interact with mucus and improve permeation. These results indicate the emerging role of large pore silica nanoparticles as promising platforms for oral delivery of biologics such as exenatide.

Carbon nanotube scaffolds as emerging nanoplatform for myocardial tissue regeneration: A review of recent developments and therapeutic implications.

Myocardial infarction (cardiac tissue death) is among the most prevalent causes of death among the cardiac patients due to the inability of self-repair in cardiac tissues. Myocardial tissue engineering is regarded as one of the most realistic strategies for repairing damaged cardiac tissue. However, hindrance in transduction of electric signals across the cardiomyocytes due to insulating properties of polymeric materials worsens the clinical viability of myocardial tissue engineering. Aligned and conductive scaffolds based on Carbon nanotubes (CNT) have gained remarkable recognition due to their exceptional attributes which provide synthetic but viable microenvironment for regeneration of engineered cardiomyocytes. This review presents an overview and critical analysis of pharmaceutical implications and therapeutic feasibility of CNT based scaffolds in improving the cardiac tissue regeneration and functionality. The expository analysis of the available evidence revealed that inclusion of single- or multi-walled CNT into fibrous, polymeric, and elastomeric scaffolds results in significant improvement in electrical stimulation and signal transduction through cardiomyocytes. Moreover, incorporation of CNT in engineering scaffolds showed a greater potential of augmenting cardiomyocyte proliferation, differentiation, and maturation and has improved synchronous beating of cardiomyocytes. Despite promising ability of CNT in promoting functionality of cardiomyocytes, their presence in scaffolds resulted in substantial improvement in mechanical properties and structural integrity. Conclusively, this review provides new insight into the remarkable potential of CNT aligned scaffolds in improving the functionality of engineered cardiac tissue and signifies their feasibility in cardiac tissue regenerative medicines and stem cell therapy.

Recent advances in the role of supramolecular hydrogels in drug delivery.

INTRODUCTION: Supramolecular hydrogels, formed by noncovalent crosslinking of polymeric chains in water, constitute an interesting class of materials that can be developed specifically for drug delivery and biomedical applications. The biocompatibility, stimuli responsiveness to various external factors, and powerful functionalization capacity of these polymeric networks make them attractive candidates for novel advanced dosage form design. AREAS COVERED: This review summarizes the significance of supramolecular hydrogels in various biomedical and drug delivery applications. The recent advancement of these hydrogels as potential advanced drug delivery systems (for gene, protein, anticancer and other drugs) is discussed. The importance of these hydrogels in biomedical applications, particularly in tissue engineering, biosensing, cell-culture research and wound treatment is briefly described. EXPERT OPINION: The use of supramolecular hydrogels in drug delivery is still in very early stages. However, the potential of such a system is undeniably important and very promising. A number of recent studies have been conducted, which mainly focus on the use of cyclodextrin-based host-guest complex as well as other supramolecular motifs to form supramolecular hydrogels for delivery of various classes of drugs, therapeutic agents, proteins and genes. However, there are still plenty of opportunities for further development in this area for drug delivery and other biomedical applications.

Synthesis of a novel acrylated abietic acid-g-bacterial cellulose hydrogel by gamma irradiation.

Acrylated abietic acid (acrylated AbA) and acrylated abietic acid-grafted bacterial cellulose pH sensitive hydrogel (acrylated AbA-g-BC) were prepared by a one-pot synthesis. The successful dimerization of acrylic acid (AA) and abietic acid (AbA) and grafting of the dimer onto bacterial cellulose (BC) was confirmed by 13C solid state NMR as well as FT-IR. X-ray diffraction analysis showed characteristic peaks for AbA and BC; further, there was no effect of increasing amorphous AA content on the overall crystallinity of the hydrogel. Differential scanning calorimetry revealed a glass transition temperature of 80°C. Gel fraction and swelling studies gave insight into the features of the hydrogel, suggesting that it was suitable for future applications such as drug delivery. Scanning electron microscopy observations showed an interesting interpenetrating network within the walls of hydrogel samples with the lowest levels of AA and gamma radiation doses. Cell viability test revealed that the synthesized hydrogel is safe for future use in biomedical applications.

A review of bacterial cellulose-based drug delivery systems: their biochemistry, current approaches and future prospects.

OBJECTIVES: The field of pharmaceutical technology is expanding rapidly because of the increasing number of drug delivery options. Successful drug delivery is influenced by multiple factors, one of which is the appropriate identification of materials for research and engineering of new drug delivery systems. Bacterial cellulose (BC) is one such biopolymer that fulfils the criteria for consideration as a drug delivery material. KEY FINDINGS: BC showed versatility in terms of its potential for in-situ modulation, chemical modification after synthesis and application in the biomedical field, thus expanding the current, more limited view of BC and facilitating the investigation of its potential for application in drug delivery. SUMMARY: Cellulose, which is widely available in nature, has numerous applications. One of the applications is that of BC in the pharmaceutical and biomedical fields, where it has been primarily applied for transdermal formulations to improve clinical outcomes. This review takes a multidisciplinary approach to consideration of the feasibility and potential benefits of BC in the development of other drug delivery systems for various routes of administration.