Drug Delivery Research Research Articles

Evaluation of GHK peptide–heparin interactions in multifunctional liposomal covering

Small biospecific peptides with defined chemical structure and cellular responses are promising alternatives to full-length therapeutic proteins. Identification of these peptides solely or in combination with other bioactive factors and determination of their targets are of substantial interest in current drug delivery research. This study is aimed at the development of new liposomal formulations of ECM-derived GHK peptide known for its multiple regeneration-related activities but poorly recognized cellular targets. In situ association of membranotropic GHK derivative with unilamellar liposomes was performed to prepare GHK-modified liposomes with defined properties. According to DLS, the GHK component on the liposomal surface interacted with heparin in a specific manner compared to other polysaccharides and RGD counterpart, whereas ITC analysis of such interactions was complicated. The results provide a useful tool for screening of bio-interactions of synthetic peptide-presenting liposomes by the DLS technique. They were also employed to produce a multi-functional nanosized GHK-heparin covering for liposomes. The resulting composite liposomes possessed low size dispersity, increased anionic charge, and mechanical rigidity. The heparin component significantly promoted the accumulation of GHK-modified liposomes in 3T3 fibroblasts so that the composite liposomes exhibited the highest cell-penetrating activity. Furthermore, the latter formulation stimulated cell proliferation and strongly inhibited ROS production and GSH depletion under oxidative stress conditions. Together, the results support that cell-surface glycosaminoglycans can be involved in GHK-mediated liposomal delivery, which can be further greatly enhanced by association with heparin. The composite liposomes with GHK-heparin covering can be considered as an advanced GHK-based formulation for therapeutic and cosmeceutical applications.

Drug-delivery research and much more: interview with Dan Peer.

Drug-delivery research and much more: interview with Dan Peer.

Special issue on drug delivery research in Turkey

Special issue on drug delivery research in Turkey

Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs

Exosomes, as promising vehicles, have been widely used in the research of oral drug delivery, but the generally low drug loading efficiency of exosomes seriously limits its application and transformation. In this study, we systematically investigated the effects of drug loading methods and physicochemical properties (lipophilicity and molecular weight) on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions. Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method, drug lipophilicity, drug molecular weight and exosome/drug proportions. Of note, we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes, which was attributed to the efficient loading capacity and sustained release behavior. Furthermore, milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs (octreotide, exendin-4 and salmon calcitonin). Collectively, our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

A Review on Microparticles Drug Delivery System

Abstract: Multiparticulate drug delivery methods frequently include microparticles, microspheres, and microcapsules, which have both medical and technological advantages. Microparticles are employed as multiunit drug delivery systems with welldefined physiological and pharmacokinetic benefits to increase efficacy, tolerance, and patient compliance. Their sizes range from 1 to 1000 m. In the creation of microparticles for drug delivery research, a variety of polymers have been used to increase therapeutic effectiveness while lowering side effects. Microparticles today are made of polymers, ceramic, and glass. Microparticles are more stable in the biological milieu than liposomes are. Surface-linked targeting moiety can be built into microparticles. In order to administer drugs to specific areas, this technique is employed. For controlled and long-term release, microparticles are also utilised. To treat many sick states such ophthalmic disorders, cancer, cardiac diseases, and inflammation, macromolecules are encapsulated inside microparticles. This review covers the pros, cons, types of microparticles, preparation method, evaluation of microparticles, and applications.

Physical Assessment and formulation development of Dome Matrix Controlled Release tablet of Diclofenac Sodium

In the last fifteen years where have significant acceleration in drug delivery research. In the early days of controlled release, development of pharmaceutical formulations was more idealized, with emphasis on the attainment of the illusive “zero-order release behavior”. When analyzing the swelling and release behavior of the Dome Matrix systems, it was demonstrated that the swelling behavior of the curved surfaces of the matrices strongly affected the drug release kinetics. The controlled release Dome matrix tablets containing Diclofenac sodium were prepared using a wet granulation process and polymers used xanthan gum, HPMC and Eudragit. Two different formulations were prepared; in first formulation the ratio was kept 60% active ingredient and 40% polymers subsequently in 2nd formulation 55% active ingredient 45% polymers. Precompression test angle of repose, Hausner’s ratio, Bulk Density, Tapped Density, Car’s Index were checked according to the specified standard procedure. All Physical Characteristics of dome tablets were analyzed. Drug release pattern was also analyzed by using USP apparatus II paddle method. The hardness, weight fluctuation, thickness, friability, drug content homogeneity, and in-vitro dissolution investigations of the manufactured controlled release tablets. All were examined and found within acceptable range. The F1 and F2 formulations performed well in tests and had a continuous drug release. The findings of this study showed that a polymer could be successfully used to formulate Diclofenac sodium Dome matrix tablets. The drug release was extended for 8 to 12 hours in all formulations using a drug to polymer ratio of 60:40, 55:45. The formulations are proved to have efficient drug release time. Keywords: Diclofenac sodium, Dome Matrix, Eudragit, Control release, Xanthan gum.

Moringa oleifera gum capped MgO nanoparticles: Synthesis, characterization, cyto- and ecotoxicity assessment

Nano-based drug delivery research is increasing due to the therapeutic applications for human health care. However, traditional chemical capping-based synthesis methods lead to unwanted toxicity effects. Hence, there is an urgent need for green synthesis-based and biocompatible synthesis methods. The current work describes for the first time the green synthesis of Moringa gum-capped MgO nanoparticles (Mgm-MgO NPs). Their antioxidant activity, hemolysis potential, cytotoxicity, phytotoxicity, toxicity by chorioallantoic membrane (CAM) chick embryo assay and in vivo toxicity in zebrafish embryos were described. The Mgm-MgO NPs exhibited significant antioxidant activity. The Mgm-MgO NPs at 500 μg/ml produced significant hemolysis (72.54 %), while lower concentrations did not. Besides, the cytotoxicity assessment of the Mgm-MgO NPs was conducted in PA-1 cells from human ovarian teratocarcinoma by MTT assay. The Mgm-MgO NPs (0.1–500 μg/ml) considerably reduced the viability of PA-1 cells. Furthermore, Mgm-MgO NPs had no significant effect on seed germination but had a significant effect on root and shoot length of mungbean (Vigna radiata). Additionally, the CAM assay was used to analyze the antiangiogenic potential of Mgm-MgO NPs, exhibiting no significant alterations after 72 h. Finally, the zebrafish embryotoxicity assay revealed that the Mgm-MgO NPs (0.1–500 μg/ml) did not affect morphology, mortality or survival rate.

Silymarin and Vanillic Acid Silver Nanoparticles Alleviate the Carbon Tetrachloride-Induced Nephrotoxicity in Male Rats

Natural copolymer (e.g., chitosan-loaded) and synthetic (e.g., silver nitrate-loaded) nanopolymers have many medical applications in drug delivery research for enhancing the effectuality of traditional medicine. This study aimed to investigate the potential protective activity of vanillic acid, silver nanoparticles (AgNPs) of vanillic acid, and silymarin against carbon tetrachloride (CCl4)-induced nephrotoxicity in male rats. Rats were divided into five groups; the first group (G1) was a negative control, and the other rats were treated intraperitoneally with CCl4 to induce kidney toxicity twice weekly, and then divided into four groups, G2 was a positive control and left without treatment, the third group was treated with vanillic acid, the fourth (G4) was treated with vanillic acid-AgNPs, and the fifth (G5) was treated with silymarin. In G2, renal function indices (urea, creatinine, and uric acid) showed elevated levels indicating renal toxicity. Na, K, and Ca ions were decreased, whereas Cl− was increased. Antioxidants (glutathione S-transferase, glutathione reduced, total antioxidant capacity, superoxide dismutase, and catalase) were decreased, whereas lipid peroxidation was increased in the kidney tissue homogenate. IL1 was increased, whereas CYP-450 was decreased. In the treated group, all biochemical and renal tissue texture were alleviated as a result of treatment with vanillic acid in G3, vanillic acid AgNPs in G4, and silymarin in G5. Vanillic acid AgNPs and silymarin treatment in G4 and G5, respectively, were more efficient than vanillic acid in G5 in protecting the kidneys against CCl4-induced nephrotoxicity.

Stimuli-Responsive Boron-Based Materials in Drug Delivery.

Drug delivery systems, which use components at the nanoscale level as diagnostic tools or to release therapeutic drugs to particular target areas in a regulated manner, are a fast-evolving field of science. The active pharmaceutical substance can be released via the drug delivery system to produce the desired therapeutic effect. The poor bioavailability and irregular plasma drug levels of conventional drug delivery systems (tablets, capsules, syrups, etc.) prevent them from achieving sustained delivery. The entire therapy process may be ineffective without a reliable delivery system. To achieve optimal safety and effectiveness, the drug must also be administered at a precision-controlled rate and the targeted spot. The issues with traditional drug delivery are overcome by the development of stimuli-responsive controlled drug release. Over the past decades, regulated drug delivery has evolved considerably, progressing from large- and nanoscale to smart-controlled drug delivery for several diseases. The current review provides an updated overview of recent developments in the field of stimuli-responsive boron-based materials in drug delivery for various diseases. Boron-containing compounds such as boron nitride, boronic acid, and boron dipyrromethene have been developed as a moving field of research in drug delivery. Due to their ability to achieve precise control over drug release through the response to particular stimuli (pH, light, glutathione, glucose or temperature), stimuli-responsive nanoscale drug delivery systems are attracting a lot of attention. The potential of developing their capabilities to a wide range of nanoscale systems, such as nanoparticles, nanosheets/nanospheres, nanotubes, nanocarriers, microneedles, nanocapsules, hydrogel, nanoassembly, etc., is also addressed and examined. This review also provides overall design principles to include stimuli-responsive boron nanomaterial-based drug delivery systems, which might inspire new concepts and applications.

Drug delivery as a sustainable avenue to future therapies

Climate change and the need for sustainable, technological developments are the greatest challenges facing humanity in the coming decades. To address these issues, in 2015 the United Nations have established 17 Sustainable Development Goals. Anthropogenic climate change will not only affect everyone personally in the coming years, it will also reinforce the need to become more sustainable within drug delivery research. In 2021, I was appointed professor for pharmaceutical biology at the Friedrich-Alexander-University Erlangen-Nürnberg. Our research is at the interface between developing biogenic therapies and understanding of bacterial infections. In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I would like to underline the need for future sustainable approaches in our research area, by highlighting selected examples from the fields of infection research, natural product characterisation and extracellular vesicles. My aim is to put into perspective current issues for these research topics, but also encourage our current student-training framework to contribute to education for sustainable development. This contribution is a personal statement to increase the overall awareness for sustainability challenges in drug delivery and beyond.

Bio-Inspired Drug Delivery Systems: From Synthetic Polypeptide Vesicles to Outer Membrane Vesicles

Nanomedicine is a broad field that focuses on the development of nanocarriers to deliver specific drugs to targeted sites. A synthetic polypeptide is a kind of biomaterial composed of repeating amino acid units that are linked by peptide bonds. The multiplied amphiphilicity segment of the polypeptide could assemble to form polypeptide vesicles (PVs) under suitable conditions. Different from polypeptide vesicles, outer membrane vesicles (OMVs) are spherical buds of the outer membrane filled with periplasmic content, which commonly originate from Gram-negative bacteria. Owing to their biodegradability and excellent biocompatibility, both PVs and OMVs have been utilized as carriers in delivering drugs. In this review, we discuss the recent drug delivery research based on PVs and OMVs. These related topics are presented: (1) a brief introduction to the production methods for PVs and OMVs; (2) a thorough explanation of PV- and OMV-related applications in drug delivery including the vesicle design and biological assessment; (3) finally, we conclude with a discussion on perspectives and future challenges related to the drug delivery systems of PVs and OMVs.

Pharmacokinetic Study of Triptolide Nanocarrier in Transdermal Drug Delivery System-Combination of Experiment and Mathematical Modeling.

Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the "first pass effect" of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components of Tripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin-blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three-layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery.

Development of Rabbit Brain Tumor Model Using VX2 Cells and Verification with the MRI in Neuroradiologic Research

To evaluate the development, location, and volume of a VX2 carcinoma using four inoculation methods in a rabbit brain. Inoculation of a VX2 cell suspension was performed 1) on the appointed day, 2) seven days after storing a VX2 carcinoma in a freezer or 3) seven days after storing a VX2 carcinoma in a deep freezer after sacrificing the donor rabbits. 4) Without sacrificing the rabbits, the VX2 cell suspension was obtained using a gun biopsy, inoculation was performed on the appointed day. MR imaging was performed 10 days after inoculation. Brain tissues were obtained the day after. The development, location, and volume of the tumor were evaluated. Seventeen of the 18 rabbits inoculated on the appointed day developed tumors (average tumor volume, 106.32 mm3). One of five inoculated seven days after storing the VX2 tumor in the freezer, and three of five inoculated seven days after storing the VX2 tumor in the deep freezer developed tumors. Inoculation with a VX2 cell suspension obtained with a gun biopsy from five rabbits revealed development of tumors in only two rabbits. The tumors mostly developed in the superficial cortex. TVX2 rabbit brain tumor model is easy to develop and revealed variable reproducibility. This model can be applicable in radiologic imaging, treatment planning, interventional treatment and drug delivery research. VX2 cell can be successfully innoculated into the brain using variable methods under researcher's variable conditions.

Folic Acid-Functionalized Albumin/Graphene Oxide Nanocomposite to Simultaneously Deliver Curcumin and 5-Fluorouracil into Human Colorectal Cancer Cells: An In Vitro Study.

Nowadays, due to various inherent properties, graphene-based nanoparticles are widely used in drug delivery research. On the other hand, folate receptors are highly expressed on the surface of human tumor cells. In this work, to enhance the 5-fluorouracil (5FU) and curcumin (Cur) effects on colon cancer, we constructed a folic acid- (FA-) modified codelivery carrier based on graphene nanoparticles (GO-Alb-Cur-FA-5FU). The HUVEC and HT-29 were selected for evaluating the antitumor effect of the prepared nanocarriers. The structure of nanocarriers was characterized by FTIR spectroscopy, X-ray diffraction analysis, TEM microscopy, and a DLS analyzer. The efficiency of the prepared carrier was evaluated by fluorescence microscopy using Annexin V and the PI kit. The cytotoxicity of the carrier's component individually and the efficacy of the drug carrier GO-Alb-Cur-FA-5FU were assessed by MTT. The results of the pharmacological tests indicated that the new nanoparticles cause increased apparent toxicity in HT-29 cells. The apoptosis rate of the HT-29 and HUVEC cells treated with IC50 values of GO-Alb-Cur-FA-5FU for 48 h was higher than the cells treated with IC50 values of 5FU and Cur individually, which indicated the greater inhibitory efficacy of GO-Alb-Cur-FA-5FU than free drugs. The designed GO-Alb-CUR-FA-5FU delivery system can be applied for targeting colon cancer cells and can be severe as a potential candidate for future drug development.

Gram-Negative Bacteria's Outer Membrane Vesicles.

Outer membrane vesicles (OMVs) are spherical bilayered nanoparticles derived from the outer layer of Gram-negative bacteria. Bacteria communicate with nearby bacteria, their environment, and the cells of their host by secreting OMVs, which are essential for their survival. OMVs also play a critical role in bacterial pathogenesis since they are loaded with virulence factors, toxins, and enzymes. OMVs may modulate the immune response of the host by initiating inflammation through cytokine production and activating the innate immune response. OMVs also contribute to the resistance of bacteria to antibiotics by carrying antibiotic-degrading enzymes and acting as natural protection barriers. Concerns have also been raised regarding OMVs mediating the transfer of antibiotic resistance. Due to their advantageous properties, OMVs are attractive platforms for vaccine discovery and drug delivery research. In this review, we discuss the fundamental structure and biogenesis mechanisms of OMVs as well as their multifaceted roles in bacterial infection pathogenesis and host immune responses. We also discuss application examples of OMVs.

A systemic review on development of mesoporous nanoparticles as a vehicle for transdermal drug delivery.

Recent advances in drug delivery technologies utilizing a variety of carriers have resulted in a paradigm shift in the current approach to diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) were developed in response to the need for materials with high thermal, chemical, and mechanical properties. The synthesis, ease of surface functionalization, tunable pore size, large surface area, and biocompatibility of MSNs make them useful in a variety of biomedical applications such as drug delivery, theranostics, and stem cell research. In addition, MSNs have a high capability of delivering actives ranging from small molecules such as drugs and amino acids to larger peptides, vaccines, and antibodies in general. Moreover, MSN-based transdermal delivery has sparked a lot of interest because of the increase in drug stability, permeation, and ease of functionalization. The functionalization of MSNs plays an important role in the efficient delivery of therapeutic agents in a highly controlled manner. This review introduced dermal and transdermal drug delivery systems, explained the anatomy of the skin, and summarized different barriers that affect the transdermal delivery of many therapeutic agents. In addition, the fundamentals of MSNs together with their physicochemical properties, synthesis approaches, raw materials used in their fabrication, and factors affecting their physicochemical properties will be covered. Moreover, the applications of MSNs in dermal and transdermal delivery, the biocompatibility of MSNs in terms of toxicity and safety, and biodistribution will be explained with the help of a detailed literature review. The review is covering the current and future perspectives of MSNs in the pharmaceutical field with therapeutic applications.

OCULAR DRUG DELIVERY SYSTEMS: AN OVERVIEW

The treatment for the ophthalmic diseases are topical route because of the various ocular barrier. Ocular drug delivery systems are considered as major challenges by today’s pharmacologist and formulation scientist. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery techniques, which may surpass these barriers and maintain drug levels in tissues. There are many eye ailments which affected to eye and one can loss the eye sight also. Therefore, many ophthalmic drug delivery systems are available. These are classified as conventional and non- conventional (newer) drug delivery systems. Most commonly available ophthalmic preparations are eye drops and ointments about 70% of the eye dosage formulations in market. So overcome to these problems newer pharmaceutical ophthalmic formulation such as in-situ gel, nanoparticle, liposome, nanosuspension, microemulsion, intophoresis and ocular inserts have been developed in last three decades increase the bioavailability of the drug as a sustained and controlled manner.

Antibacterial, antifungal, antidiabetic, and antioxidant activities potential of Coleus aromaticus synthesized titanium dioxide nanoparticles

The nanoparticles based drug delivery and treatment related research has been increased significantly in the recent years. Hence, the antibacterial, antifungal, and antioxidant activity potential of pre synthesized and characterized Titanium dioxide nanoparticles (TiO2 NPs) were investigated in this study through respective standard protocols. Interestingly, the obtained results revealed that TiO2 NPs have concentration dependent antibacterial activity against bacterial pathogens such as E. coli, P.mirabilis, V. cholerae, P. aeruginosa, S. typhimurium, and S. aureus at 100 μg mL−1 concentration. Furthermore, these TiO2 NPs showed remarkable antifungal activity against aspergillosis causing fungal pathogens such as A. niger, A. fumigatus, A. nidulans, and A. flavus at 100 μg mL−1 concentration. α-glucosidase. This TiO2 NPs also effectively inhibit the α-amylase (17%) and α-Glucosidase (37%) enzyme activity at 100 μg mL−1 dosage. The DPPH assay revealed that TiO2 NPs effectively scavenge DPPH free radicals by up to 89% at 100 μg mL−1 concentration, which was comparable to butylated hydroxytoluene (96%). These results suggest that the plant-based TiO2 NPs have remarkable in-vitro antibacterial, antifungal, and antioxidant activity. These may be considered for additional in-vitro and in-vivo experiments to assess their potential biomedical applications.

Multifunctional Nanoparticles for Organelle-Specific Targeted Drug Delivery in Cancer Therapy

Abstract:Successful drug delivery with a carrier into the targeted organelles (nucleus, mitochon-dria, lysosomes, etc.) is vital for achieving effective disease treatment. Nanoparticle (NP) based drug delivery systems (NDDSs) depend on targeted delivery and are mainly focused on cell-membrane targeting. In this review, we summarize research on multifunctional NPs with organelle-specific drug delivery. Different effective strategies are proposed for these nanoparticles functional-izing by altering their chemical composition or by functional groups grafting onto their surface for improving the ability of organelle targeting. Only when the released concentration of drugs be-comes high enough will they interact with specific organelles by molecular targets to induce apop-tosis of tumor cells. One of the prime goals for drug delivery research targeted is Organelle-specific delivery.

Elucidating a Potential Mechanism of Permeability Enhancer Sodium N-[8-(2-hydroxybenzoyl) amino] Caprylate in Rats: Evidence of Lymphatic Absorption of Cyanocobalamin using the Mesenteric Lymph Duct Cannulated Rat

Oral administration is the most popular and convenient route for drug delivery, yet the success of oral drug delivery is dependent on the ADME properties of the drug. Among those ADME properties, permeability is considered one of the key attributes for successful oral drug absorption. Hence, the utilization of permeability enhancers to improve drug oral absorption is an important area of research in drug delivery. A multitude of data suggests that sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) is an effective permeability enhancer. Despite its success, the mechanism of how SNAC works to enhance the oral absorption of compounds is poorly understood. To better understand how SNAC worked, we investigated the hypothesis of SNAC promotes lymphatic absorption of target compounds. In this study, cyanocobalamin was used as the model compound and mesenteric lymph duct cannulated rats were used to investigate its absorption with or without SNAC. The present study demonstrated that SNAC enhanced the lymphatic absorption of cyanocobalamin when the two were co-dosed in rats. Furthermore, levels of SNAC in lymph fluid and the systemic circulation were higher when co-dosed with cyanocobalamin.