Advanced Delivery Systems Research Articles

Review on Targeted Drug Delivery Carriers Used in Nanobiomedical Applications

Targeted drug delivery (TDD) is an advanced and smart method of delivering drugs to the patients in a targeted sequence that increases the concentration of delivered drug only at the targeted body part of interest (organs/tissues/cells). This will in turn enhance efficacy of treatment by reducing side effects and the required dose of the drug. TDD ensures a certain defined minimally required constant amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body thereby avoiding any damage to the healthy tissue via the drug. Various drug carriers that are envisaged in advanced delivery systems are soluble polymers, inorganic nanoparticles, magnetic nanoparticles, biodegradable microsphere polymers (synthetic and natural), neutrophils, fibroblasts, artificial cells, lipoproteins, liposomes, micelles and immune micelle. In selecting such a vehicle, important factors to consider are chemical and physical properties drugs, side effects or cytotoxicity to healthy cells, route to be taken for the delivery of the drug, the targeted site, and the disease. As such, TDD formulations are prepared by considering the specific properties of target cells, nature of markers or transport carriers or vehicles, which convey drug to specific receptors, and ligands and physically modulated components.

CRISPR/Cas Genome Editing and Precision Plant Breeding in Agriculture.

Enhanced agricultural production through innovative breeding technology is urgently needed to increase access to nutritious foods worldwide. Recent advances in CRISPR/Cas genome editing enable efficient targeted modification in most crops, thus promising to accelerate crop improvement. Here, we review advances in CRISPR/Cas9 and its variants and examine their applications in plant genome editing and related manipulations. We highlight base-editing tools that enable targeted nucleotide substitutions and describe the various delivery systems, particularly DNA-free methods, that have linked genome editing with crop breeding. We summarize the applications of genome editing for trait improvement, development of techniques for fine-tuning gene regulation, strategies for breeding virus resistance, and the use of high-throughput mutant libraries. We outline future perspectives for genome editing in plant synthetic biology and domestication, advances in delivery systems, editing specificity, homology-directed repair, and gene drives. Finally, we discuss the challenges and opportunities for precision plant breeding and its bright future in agriculture.

Development of an Advanced Delivery System of CSKSSDYQC Peptide Modified N-Trimethyl Chitosan Nanoparticles for Oral Delivery of Gemcitabine

Development of an Advanced Delivery System of CSKSSDYQC Peptide Modified N-Trimethyl Chitosan Nanoparticles for Oral Delivery of Gemcitabine

Unraveling Polymeric Nanoparticles Cell Uptake Pathways: Two Decades Working to Understand Nanoparticles Journey to Improve Gene Therapy.

Polymeric nanoparticles have aroused an increasing interest in the last decades as novel advanced delivery systems to improve the treatment of many diseases. Hard work has been performed worldwide designing and developing polymeric nanoparticles using different building blocks, which target specific cell types, trying to avoid bioaccumulation and degradation pathways. The main handicap of the design is to understand the final fate and the journey that the nanoparticle will follow, which is intimately ligated with the chemical and physical properties of the nanoparticles themselves and specific factors of the targeted cells. Although the huge number of published scientific articles regarding polymeric nanoparticles for biomedical applications, their use in clinics is still limited. This fact could be explained by the limited data reporting the interaction of the huge diversity of polymeric nanoparticles with cells. This knowledge is essential to understand nanoparticle uptake and trafficking inside cells to the subcellular target structure.In this chapter, we aim to contribute to this field of knowledge by: (1) summarizing the polymeric nanoparticles properties and cellular factors that influence nanoparticle endocytosis and (2) reviewing the endocytic pathways classified as a function of nanoparticle size and as a function of the receptor playing a role. The revision of previously reported endocytic pathways for particular polymeric nanoparticles could facilitate scientist involved in this field to easily delineate efficient delivery systems based on polymeric nanoparticles.

Microcontainers for protection of oral vaccines, in vitro and in vivo evaluation

Oral vaccines are highly desirable due to simple logistics, mass vaccination potential and for mucosal immunity. Subunit vaccines are preferred due to high safety, but are inherently difficult to deliver orally, thus providing motivation for the use of advanced oral delivery systems. Polymeric devices in micrometer size (microcontainers) were tested here for this purpose. Microcontainers were loaded with a vaccine consisting of spray dried cubosomes with OVA and Quil-A, and coated with a pH-sensitive lid for oral delivery to C57Bl/6 mice. The microcontainers were explored in vitro and in vivo for their potential as oral vaccine delivery system in an oral prime-boost setting and as an oral booster after a subcutaneously injected prime. The residence time of microcontainers in the small intestine was less than one hour. Eudragit® L100–55 was therefore chosen as lid material on the microcontainers as it remained stable in vitro at pH 4.7, which simulated the maximal pH of the stomach, and allowed release of the cubosomes within 30–60 min at pH 6.6, which simulated the mean pH of the distal half of the small intestine. In vitro small angle X-ray scattering showed that cubosomes dissolved in small intestinal fluid when not confined in microcontainers but when loaded into microcontainers they were released as hexosomes. However, while microcontainers could protect and release particles with OVA and Quil-A within relevant time frames in vitro, an immune response was not elicited in vivo after oral administration. Nonetheless, some effect was observed when the microcontainers were used to deliver oral boosters following a subcutaneous prime. This work indicates that oral vaccination with subunit vaccines has potential when combined with a parenteral prime and that oral delivery systems like microcontainers may be used to increase the potency of vaccines with low oral immunogenicity.

DIABETIC RETINOPATHY: AN INCLUSIVE REVIEW ON CURRENT TREATMENT AND MANAGEMENT APPROACHES

Diabetic retinopathy (DR) is a complication which occurs due to diabetes mellitus leading to loss of vision and hindering the quality of patient life by damaging the layer of retina at the posterior segment of the eye. According to the survey around 285 million peoples are suffering from visual loss out of these 65% of people are more than 50 years old and 82% of blind patients are more than 50 years old. The diseases that occur in the posterior segment of the eye like, cytomegalovirus retinitis, posterior uveitis, age related macular degeneration and diabetic retinopathy needs a novel delivery system that can improve the concentration of drugs that reaches posterior segment of the eye. The development of new drug delivery system gained more importance in the field of research in which nanotechnology is the most considered approach. The nanotechnology-based systems such as nanoparticles, nanoliposomes, niosomes, nanomicelles, nanoemulsions, nanogels, cyclodextrins, dendrimers, and quantum dots are developed as a new formulation for drug delivery. The rationale behind the nanoparticle systems is its ability to formulate a sustained, controlled release dosage form, painless, safe, non-invasive system to overcome the major barriers in the treatment of DR. Based on the nanoparticles, some approaches are exploited for more effective conveyance of drug toward the posterior segment. Thus, these advanced delivery systems progress the therapeutic efficacy of the drug and patient’s obedience and life quality. In this review, the new therapeutic treatments and their managements were discussed and methods of drug delivery to reach the posterior segment of eye.

New Advances in General Biomedical Applications of PAMAM Dendrimers.

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named ‘starburst polymers’. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.

Rapid, Scalable Assembly and Loading of Bioactive Proteins and Immunostimulants into Diverse Synthetic Nanocarriers Via Flash Nanoprecipitation.

Nanomaterials present a wide range of options to customize the controlled delivery of single and combined molecular payloads for therapeutic and imaging applications. This increased specificity can have significant clinical implications, including decreased side effects and lower dosages with higher potency. Furthermore, the in situ targeting and controlled modulation of specific cell subsets can enhance in vitro and in vivo investigations of basic biological phenomena and probe cell function. Unfortunately, the required expertise in nanoscale science, chemistry and engineering often prohibit laboratories without experience in these fields from fabricating and customizing nanomaterials as tools for their investigations or vehicles for their therapeutic strategies. Here, we provide protocols for the synthesis and scalable assembly of a versatile non-toxic block copolymer system amenable to the facile formation and loading of nanoscale vehicles for biomedical applications. Flash nanoprecipitation is presented as a methodology for rapid fabrication of diverse nanocarriers from poly(ethylene glycol)-bl-poly(propylene sulfide) copolymers. These protocols will allow laboratories with a wide range of expertise and resources to easily and reproducibly fabricate advanced nanocarrier delivery systems for their applications. The design and construction of an automated instrument that employs a high-speed syringe pump to facilitate the flash nanoprecipitation process and to allow enhanced control over the homogeneity, size, morphology and loading of polymersome nanocarriers is described.

Finding the ideal polyethylenimine-plasmid DNA system for co-delivery of payloads in cancer therapy.

Researchers still hold for the development of a safety and advanced delivery system able of efficient therapeutic action. The co-delivery of different payloads is part of this strategy and has already demonstrated to be a valuable tool against the most severe diseases. In the pursuit of an "ideal" drug/gene co-delivery vector for cancer therapy, we present a complete comparison study of different morphology and molecular weight polyethylenimine (PEI)/p53 encoding plasmid DNA (pDNA) polyplexes. Besides pDNA, also methotrexate (MTX) has been loaded into PEI/pDNA nanoparticles. The polyplexes have been characterized in terms of morphology, size, surface charges, loading/encapsulation efficiencies and toxicity. Although the nature of PEI can influence these properties, they deeply vary with the polymer nitrogen to pDNA phosphate (N/P) ratio. The transfection of HeLa cells mediated by PEI/pDNA/MTX vectors leads to both the release of MTX and the p53 protein expression. Modelling of MTX release kinetics brings valuable information concerning drug delivery mechanism. Moreover, the success of transfection is dependent on the nature of PEI and, mainly, on the N/P ratio used in the formulation of polyplexes. This work represents a great contribution for the design and development of innovative PEI based carriers for the most challenging biomedical applications.

Development and Characterization of Solid Lipid Nanoparticles Containing Herbal Extract: In Vivo Antidepressant Activity.

In alternate systems of medicine like Ayurveda and traditional Chinese medicine, Hibiscus rosa sinensis and its extracts have been traditionally prescribed for their antidepressant activity. Crude extracts and rudimentary formulations approaches are good for proof-of-concept studies; however, these formulations are fraught with problems like poor oral bioavailability and high variability between subjects. Systematic drug delivery approaches could prove effective in addressing some of these problems. In this study, we report the development of Hibiscus rosa sinensis extract loaded solid lipid nanoparticles (HSLNs) using glycerol monostearate or beeswax as lipids. The HSLNs were evaluated for their size, surface charge, and morphology. The optimized HSLNs were tested for antidepressant activity in male Swiss albino mice. It was found that, with the optimized procedure, HSLNs of ~175 nm, carrying negative charge and nearly spherical shape, could be obtained. The in vivo test results suggested that there were marked differences in the immobility times of the test animals. Moreover, with HSLNs, it was found that at doses several times lower than the native crude extract dose, similar pharmacological effect could be obtained. These initial findings suggest that encapsulating phytopharmaceuticals into advanced delivery systems like solid lipid nanoparticles can be an effective strategy in improving their in vivo performance.

New Insight in Improving Therapeutic Efficacy of Antipsychotic Agents: An Overview of Improved In Vitro and In Vivo Performance, Efficacy Upgradation and Future Prospects.

Psychotic disorders are recognized as severe mental disorders that rigorously affect patient's personality, critical thinking, and perceptional ability. High prevalence, global dissemination and limitations of conventional pharmacological approaches compel a significant burden to the patient, medical professionals and the healthcare system. To date, numerous orally administered therapies are available for the management of depressive disorders, schizophrenia, anxiety, bipolar disorders and autism spectrum problems. However, poor water solubility, erratic oral absorption, extensive first-pass metabolism, low oral bioavailability and short half-lives are the major factors which limit the pharmaceutical significance and therapeutic feasibility of these agents. In recent decades, nanotechnology-based delivery systems have gained remarkable attention of the researchers to mitigate the pharmaceutical issues related to the antipsychotic therapies and to optimize their oral drug delivery, therapeutic outcomes, and patient compliance. Therefore, the present review was aimed to summarize the available in vitro and in vivo evidences signifying the pharmaceutical importance of the advanced delivery systems in improving the aqueous solubility, transmembrane permeability, oral bioavailability and therapeutic outcome of the antipsychotic agents.

The potential role of nanomedicine in lung diseases

Nanomedicine is a rapidly emerging interdisciplinary field in which medicine is coupled with nanotechnology tools and techniques for advanced therapy with the aid of molecular knowledge. Nanoscale drug delivery systems provide a platform to improve the pharmacokinetics and increase the bio-distribution of therapeutic agents to target organs, thereby resulting in improved efficacy while limiting drug toxicity. These systems have revolutionized drug delivery approaches and are exploited for therapeutic purposes to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. Several promising molecular targets that have been identified as potential therapies for acute and chronic respiratory conditions have been limited because of difficulty with delivery systems. In particular, delivery of peptides, proteins, miRNAs to the lung is an ongoing challenge. Hence, it is an attractive strategy to test potential targets by employing a nanotechnology approach. Nanobiotechnology and nanoscience can provide innovative techniques to deliver drugs targeted to the site of inflamed organs. Here we review some of the nanomedicine approaches that have been proposed and studied over the last decade to facilitate the delivery of therapeutic agents specifically for acute and chronic lung diseases. Development of nano-sized carriers including nanoparticles, or liposomes holds great potential for diagnosis and advanced delivery systems for immunomodulation in respiratory diseases; however translational studies are urgently needed to validate the use of nanotechnology for clinical applications.

Phage therapy: progress in pharmacokinetics

The concept of phage therapy exists in the history and it has been ignored for a long time, but the consequence of drug resistance in pathogen bacteria has forced the forgotten kingdom of phage therapy to be re-explored. However, for the successful implementation and acceptance of phage therapy worldwide, the number of factors need to be addressed. In pharmacology of phage therapy, pharmacodynamics is a straightforward concept, on the other hand, owing to the unique feature of phages to replicate and their high sensitivity, pharmacokinetics is rather complex. In this review, we have discussed pharmacokinetics and some recent advances in delivery systems as to achieve the therapeutically effective concentrations of phage in their activated form.

Clinical translation of microbe-based therapies: Current clinical landscape and preclinical outlook.

Next generation microbe‐based therapeutics, inspired by the success of fecal microbiota transplants, are being actively investigated in clinical trials to displace or eliminate pathogenic microbes to treat various diseases in the gastrointestinal tract, skin, and vagina. Genetically engineered microbes are also being investigated in the clinic as drug producing factories for biologic delivery, which can provide a constant local source of drugs. In either case, microbe‐therapeutics have the opportunity to address unmet clinical needs and open new areas of research by reducing clinical side effects associated with current treatment modalities or by facilitating the delivery of biologics. This review will discuss examples of past and current clinical trials that are investigating microbe‐therapeutics, both microbiome‐modulating and drug‐producing, for the treatment of a range of diseases. We then offer a perspective on how preclinical approaches, both those focused on developing advanced delivery systems and those that use in vitro microbiome model systems to inform formulation design, will lead to the realization of next‐generation microbe‐therapeutics.

Clinical and economic benefits of advanced microplegia delivery system in cardiac surgery: evidence from 250 hospitals.

Determine the impact of a second generation microplegia delivery system (MPS2) compared with traditional cardioplegia. Materials & methods: Multivariable difference-in-differences analysis using fixed effects was performed for each outcome: adverse event (AE)composite, total visit cost, medication cost, length of stay (LOS) and intensive care unit (ICU) days. A 2.25% absolute risk reduction in AE composite was found with MPS2 compared with traditional cardioplegia, which equates to relative risk reduction of 5.25%. Significant reductions in LOS and ICU days (0.1αlevel). Per case reduction of US$1231 total visit and US$192 medication costs were found in MPS2 hospitals. For hospitals with MPS2, significant reductions were seen in AEs, LOS and ICU days, which lead to reductions in total visit and medication costs.

Lipid Nanoparticles Enabling Gene Therapies: From Concepts to Clinical Utility.

Genetic drugs based on RNA or DNA have remarkable therapeutic potential as virtually any disease can be treated by silencing a pathological gene, expressing a beneficial protein, or by editing defective genes. However, therapies based on nucleic acid polymers require sophisticated delivery systems to deliver these macromolecules to the interior of target cells. In this study, we review progress in developing nonviral lipid nanoparticle (LNP) delivery systems that have attractive properties, including ease of manufacture, reduced immune responses, multidosing capabilities, larger payloads, and flexibility of design. LNP systems represent the most advanced delivery systems for genetic drugs as it is expected that an LNP-short interfering RNA (siRNA) formulation will receive clinical approval from the Food and Drug Administration (FDA) in 2018 for treatment of the hereditary condition transthyretin-mediated amyloidosis, a fatal condition for which there is currently no treatment. This achievement is largely due to the development of optimized ionizable cationic lipids, arguably the most important factor in the clinical success of LNP-siRNA. In addition, we highlight potential LNP applications, including targeting tissues beyond the liver and therapeutic approaches based on messenger RNA or Clustered Regularly Interspaced Short Palindromic Repeats/Cas.

A hepatic pDNA delivery system based on an intracellular environment sensitive vitamin E-scaffold lipid-like material with the aid of an anti-inflammatory drug

Non-viral vectors are considered to be an attractive approach for gene delivery, since an artificial material is less immunogenic and oncogenic compared to a viral vector. We previously reported on the hepatic delivery of plasmid DNA (pDNA) by using lipid-like material (an SS-cleavable and pH-activated lipid-like material: ssPalm) which mounts two hydrophobic scaffolds, proton-accepting motifs (tertiary amines), and a cleavable unit (disulfide bonding). In the present study, we report on an advanced hepatic gene delivery system that uses a new type of ssPalm derivative: ssPalmE-Paz4-C2. The hepatic transgene expression of the intravenously administrated lipid nanoparticle (LNP) that was formed with the ssPalmE-Paz4-C2 (LNPssPalmE-Paz4-C2) was significantly higher than that of conventional LNPs formed with a myristic acid-scaffold ssPalm (LNPssPalmM). However, the LNPssPalmE-Paz4-C2 particle induced a severe innate immune response that involved the production of the pro-inflammatory cytokines (IL-6 and TNFα), intracellular DNA sensor-related cytokine (IL-1β) and interferon (IFNβ), even when a pDNA free from CpG-motifs was encapsulated. The production of the pro-inflammatory cytokines and the DNA sensor-related cytokines is attributed to the combination of vitamin E scaffolds and encapsulated pDNA. The depletion of macrophages by chlodronate-encapsulating liposomes dramatically reduced inflammatory gene expression. Based on the above findings, we conclude that the use of a certain type of non-viral carrier that shows a robust gene expression activity is attended by a risk of eliciting an innate immune response. When a highly hydrophobic derivative of dexamethasone, an anti-inflammatory glucocorticoid compound, was co-loaded to the particle, this inflammatory response was relieved, and gene expression efficiency was enhanced. It is thus concluded that the co-delivery of dexamethasone and pDNA is a promising approach for reducing these risks.

Halloysite nanotubes for efficient loading, stabilization and controlled release of insulin

Hypothesis: Oral insulin administration is not actually effective due to insulin rapid degradation, inactivation and digestion by proteolytic enzymes which results in low bioavailability. Moreover insulin is poorly permeable and lack of lipophilicity. These limits can be overcome by the loading of protein in some nanostructured carrier such as halloysite nanotubes (HNTs).Experiments: Herein we propose an easy strategy to obtain HNT hybrid materials for the delivery of insulin. We report a detailed description on the thermal behavior and stability of insulin loaded and released from the HNTs hybrid by the combination of several techniques.Findings: Release experiments of insulin from the HNTs revealed the efficacy of the nanocarrier. Circular Dichroism data evidenced that the released insulin exhibits its native-like secondary structure confirming the suitability of HNT/insulin as delivery system for at least three months. The loaded nanotubes were filled into chitosan matrix with the aim to prepare bionanocomposite films that can be used for transdermal delivery. This work puts forward an efficient strategy to prepare halloysite based nanocarriers containing insulin that could be employed in several biomedical applications. The detailed description of the prepared HNT/insulin hybrid represents a fundamental point for designing advanced delivery systems.

Smartphone controlled hexapod for search rescue and payload delivery

Rudra, the robotic hexapod has 6 independent actuators that are connected to specially designed semi-circular wheelbase for rugged motion. The robotic platform can conquer any terrain with ease and versatility. The advanced payload delivery system includes one 3 DOF arm along with a capacious block inside the body of the platform. The platform can devour any terrain including grass, gravel, mud, rocks, harsh terrain, asphalt, sand. The platform has a dynamic sensor system for real-time monitoring of its surroundings and a feedback to the end user.The entire platform is controlled by an android app.

Polymeric advanced delivery systems for antineoplasic drugs: doxorubicin and 5-fluorouracil

Abstract Conventional pharmaceuticals generally display the inability to transport active ingredients directly to specific regions of the body, amongst some of their main limitations. The distribution of the drugs in the circulatory system may lead to undesired toxicity, and therefore, adverse reactions. To address this situation, a selective transport of drugs is required, that is, releasing drugs specifically to the site of action in appropriate concentrations and in the right time. To achieve this goal, it is necessary to develop delivery systems that respond to several features, such as low toxicity, optimum properties for the transport and release of the drug, as well as a long half-life in the body. This feature paper critically provides an overview of different strategies of controlled drug release for two model antineoplasic drugs, i.e. doxorubicin (DOX) and 5-fluorouracil (5-FU). Any of the presented strategies for drug release possess advantages and disadvantages, and the selection of the strategy used will depend on the targeted tissue and nature of the drug.