Bioinspired and biomimetic systems for advanced drug and gene delivery

BackgroundPolymeric drug delivery systems have been achieved great development in the last two decades. Polymeric drug delivery has defined as a formulation or a device that enables the introduction of a therapeutic substance into the body. Biodegradable and bio-reducible polymers make the magic possible choice for lot of new drug delivery systems. The future prospects of the research for practical applications has required for the development in the field.Main bodyNatural polymers such as arginine, chitosan, dextrin, polysaccharides, poly (glycolic acid), poly (lactic acid), and hyaluronic acid have been treated for polymeric drug delivery systems. Synthetic polymers such as poly (2-hydroxyethyl methacrylate), poly(N-isopropyl acrylamide)s, poly(ethylenimine)s, dendritic polymers, biodegradable and bio-absorbable polymers have been also discussed for polymeric drug delivery. Targeting polymeric drug delivery, biomimetic and bio-related polymeric systems, and drug-free macromolecular therapeutics have also treated for polymeric drug delivery. In polymeric gene delivery systems, virial vectors and non-virial vectors for gene delivery have briefly analyzed. The systems of non-virial vectors for gene delivery are polyethylenimine derivatives, polyethylenimine copolymers, and polyethylenimine conjugated bio-reducible polymers, and the systems of virial vectors are DNA conjugates and RNA conjugates for gene delivery.ConclusionThe development of polymeric drug delivery systems that have based on natural and synthetic polymers are rapidly emerging to pharmaceutical fields. The fruitful progresses have made in the application of biocompatible and bio-related copolymers and dendrimers to cancer treatment, including their use as delivery systems for potent anticancer drugs. Combining perspectives from the synthetic and biological fields will provide a new paradigm for the design of polymeric drug and gene delivery systems.

Drug delivery systems (DDS) have been the focus of intense research for several decades. Many approaches and strategies have been employed over the years, further expanding this field. For example, the advancements towards targeted drug delivery (TDD) enabled the use of DDS for diagnostic purposes. In addition, DDS research has provided the foundation for tissue engineering and theranostic systems (therapeutic systems with diagnostic properties). Drug delivery research has yielded many successes over the years with a significant amount of therapeutic and diagnostic products out in the market. Nevertheless, many challenges still remain. Herein, in this special edition, we asked various experts to review recent advancements in their field of expertise and report their latest findings. The special edition is well balanced and is comprised of 60% reviews and 40% research articles. One may find up-to-date reviews on advancements made in biomaterials, noninvasive drug delivery, drug conjugations, biosensors, diagnostics, implantable and ingestible devices, nanomaterials, cancer treatment, and endosome-derived vesicles. Additionally, research articles are provided, describing advanced new designs of microneedles (MNs), approaches to enhance tissue engineering capabilities, biomaterials, and DDS. The global market of protein- and nucleotide- based pharmaceutics accounted for $643 million in 2016, and is anticipated to reach over $8000 million by 2028. However, the use of these therapeutics is hindered by issues of immunogenicity, high molecular weight, fast renal clearance, and enzymatic degradation. For these reasons, to date, monoclonal antibodies (mAbs) are administered only via injection. Considering that, Angsantikul et al. propose the use of ionic liquid and eutectic solvent for the oral delivery of mAbs (article number 2002912). Their system reduced the mucosal viscosity and enhanced the paracellular transport of TNFα antibody in vitro. Additionally, Rondon and colleagues review the latest advancements in polymer chemistry and protein engineering in order to overcome part of these limitations (article number 2101633). Another approach to overcome these limitations is by using antibody-drug conjugates (ADCs). Accordingly, Firer and Luboshits review the recent developments employed in ADCs for the treatment of hematological malignancies (article number 2100032). They focus on the important link between the biology of the ADC and clinical efficacy, highlighting newer developments that strengthen this link to provide long-term clinical benefits. One of the most important purposes of drug delivery is achieving TDD. Dacoba and colleagues provide an overview on the concepts of passive and active targeting while exploring current venues for nanotechnology to solve the problems associated with drug delivery (article number 2009860). TDD is especially important for cancer therapy since killing cancerous cells is quite facile, but killing only cancerous cells is extremely challenging. Fu et al. review the latest strategies employed to overcome the barriers of chimeric antigen receptor T cells therapy in solid tumors (article number 2009489). Brain therapy is another challenging route for drug delivery requiring specific TDD system. To this end, Buaron et al. have developed a novel pectic galactan-based gene therapy approach that targets reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 (article number 2100643). Their biocompatible pectin galatcan-plasmid DNA complexes were selectively transfected to glial cells in cortical lesions. Moreover, Avital et al. report their interesting application for nanosized DDS—foliar delivery of siRNA for treating grapevine leafroll associated virus-3 (GLRaV-3) infection that causes major economic losses (article number 2101003). By exploiting a lipid-modified polyethylenimine carrier, they show that a single dose can knock down GLRaV-3 titer, and multiple doses keeps the viral titer at baseline, which triggers the recovery of the vine and berries. Another important aspect of drug delivery research is the development of noninvasive drug administration routes. Rahamim and Azagury review the origins of biomimetic, bioinspired, and bioengineered noninvasive DDS and achievements made in the last decade (article number 2102033). Additionally, Zhang et al. review advances in DDS that access the ear through the tympanic membrane (article number 2008701). Transdermal drug delivery is one of the most used noninvasive drug delivery routes. An exciting approach for transdermal drug delivery is microneedles (MNs). Puigmal and colleagues propose applying MNs array to treat severe burns that simultaneously sample immune cells in the interstitial fluid to diagnose the response (article number 2100128). Their MNs design enables the local delivery of pharmaceutics—the chemokine CCL22 and the cytokine IL-2—thus increasing local immuno-suppression. They found that the immune cell population in the allograft and MN were similar so they can be harvested from the MN for downstream analysis. Moreover, Li et al. have also proposed an improved MNs design where they use a biphasic dissolvable MN patch with water-insoluble backing in order to tackle insufficient drug delivery with MN (article number 2103359). Their new design enables a drug delivery efficiency of >90% into the skin within 5 min. Biomaterials are the building blocks of drug delivery, diagnostics, and tissue engineering research. Therefore, there is an ever-growing need for novel biomaterials with new functionalities and improved properties. To this end, Arun et al. present an exclusive coverage of biocompatible injectable pasty or liquid polymers without the use of any solvent for drug delivery and regenerative medicine applications (article number 2010284). Moreover, Khait et al. review novel biomaterial-based strategies used to modulate the immune response post ischemic stroke while providing their perspective on the potential clinical translation of these therapies (article number 2010674). Additionally, Redenski et al. developed a new composite tissue made of soft-tissue matrices and decellularized bone for bone defect repair (article number 2008687). The use of their novel tissue composite supported a long-term bone defect repair, as well as muscle defect bridging. These aforementioned applications and additional applications use cell-based therapeutics. The major obstacles of cell-based therapeutics are their low yields (i.e., difficult to scale-up), insufficient drug loading, and inconsistencies. For this reason, Guo et al. have developed a scaled-up and facile magnetic-based extrusion method for preparing endosome-derived vesicles (article number 2008326). An additional application of diagnostics and therapeutics is implantable and ingestible devices. In this special edition, Yang and colleagues provide an up-to-date review on the state-of-the-art of powering technologies for implantable and ingestible electronics—one of the greatest challenges for ingestible devices (article number 2009289). Welch et al. have focused their review on the complex hierarchical nano-structures and nano-materials used in biosensors and diagnostic technologies (article number 2104126). Additionally, they discuss their unique advantages and clinical applications while proposing future directions. In this special edition Nakonechny and Nisnevitch provide an up-to-date review focused on ultrasound applications used to combat infections caused by microorganisms, and to promote the local release of antimicrobial drugs from liposomes and medical implants (article number 2011042). Precise and well-controlled scaffolds are highly desired for tissue engineering and regenerative medicine purposes. For example, Dubay et al. review the recent achievements of single-cell microgels and their potential alternatives, which are used when single cell resolution is needed, for example—modular bio-inks and 3D cellular microenvironments (article number 2009946). Another challenge for implantable devices is a foreign body response (FBR). Kutner et al. review the recent advantageous technologies used to overcome the FBR effect via surface modifications and localized DDS (article number 2010929). One such surface modification is reported by Israeli et al. who developed a general and versatile technology to engineer light-responsive protein-based biomaterials (article number 2011276). These novel biomaterials—consist of azobenzene containing elastin-like polypeptides—are capable of forming self-assembled nanostructures and exhibit a reversible, light-mediated phase transition, with up to a 12 °C difference in the transition temperature. We are certain that this assemblage of reviews and research papers on the use of DDS for therapeutic and diagnostic purposes is of high interest for anyone working in this field. It provides up-to-date reviews on state-of-the-art topics and research papers with promising results to further propel drug delivery research. Understanding what has been done in the past, while learning of new approaches and techniques, is crucial for any scholar who wishes to advance their personal research. Joseph Kost D.Sc. is a University Distinguished Professor, he holds The Abraham and Bessie Zacks Chair in Biomedical Engineering and was the Dean of the Faculty of Engineering Sciences at Ben-Gurion University of the Negev (BGU). He is a member of AIMBE, NAE, CRS, and the Israel Academy of Sciences and Humanities. His research interests are in the fields of biomedical engineering, biomaterials science, controlled drug delivery, gene therapy, and ultrasound. Edith Mathiowitz is a full Professor of Medical Science and Engineering at Brown University, Department of Department of Pathology and Laboratory Medicine. She Is an AIMBE, CRS, and NAI fellow member. She founded and directed the ABC/Biotechnology Graduate Program at Brown. Her interdisciplinary research is focused on developing smart oral bioadhesive delivery systems and novel insights in polymer morphology. Her laboratory serves as an incubator for several start-up companies such as Spherics, Perosphere, and Therapyx. Aharon (Roni) Azagury is an Assistant Professor in the Department of Chemical and Biotechnology Engineering in Ariel University. He received his PhD in chemical engineering from BGU. He is a member of the CRS, ICRS, and NAI societies. His current research focuses on developing novel noninvasive biomimetic and bioinspired drug delivery systems.

Nanohybrid cerasomes: Advancements in targeted drug and gene delivery

Cyclodextrin-based supramolecular architectures: Syntheses, structures, and applications for drug and gene delivery

Silk is a natural polymer with unique physicochemical and mechanical properties which makes it a desirable biomaterial for biomedical and pharmaceutical applications. Silk fibroin (SF) has been widely used for preparation of drug delivery systems due to its biocompatibility, controllable degradability and tunable drug release properties. SF-based drug delivery systems can encapsulate and stabilize various small molecule drugs as well as large biological drugs such as proteins and DNA to enhance their shelf lives and control the release to enhance their circulation time in the blood and thus the duration of action. Understanding the properties of SF and the potential ways of manipulating its structure to modify its physicochemical and mechanical properties allows for preparation of modulated drug delivery systems with desirable efficacies. This review will discuss the properties of SF material and summarize the recent advances of SF-based drug and gene delivery systems. Furthermore, conjugation of the SF to other biomolecules or polymers for tissue-specific drug delivery will also be discussed.

To improve the performance of nanostructured calcium carbonate in gene delivery, a hydrophilic polysaccharide, alginate, was added to calcium carbonate co-precipitation systems to form alginate/CaCO(3)/DNA nanoparticles. The size and ζ-potential of the nanoparticles were measured by a zetasizer. Due to the existence of alginate chains which retarded the growth of calcium carbonate based co-precipitates, the alginate/CaCO(3)/DNA nanoparticles exhibited a decreased size and enhanced stability in the aqueous solution. To evaluate the gene and drug co-delivery ability, doxorubicin hydrochloride (DOX), a water-soluble anticancer drug, was loaded in the nanoparticles to form alginate/CaCO(3)/DNA/DOX nanoparticles. The in vitro gene transfections mediated by different nanoparticles in 293 T cells and HeLa cells were carried out, using pGL3-Luc as a reporter plasmid. With an appropriate amount of alginate, the gene transfection efficiency of alginate modified nanoparticles could be significantly enhanced as compared with the nanoparticles without alginate modification for the gene delivery systems, as well as the gene and drug co-delivery systems. The study on in vitro cell inhibition effects showed that the cell viability decreased with increasing DOX amount loaded in alginate/CaCO(3)/DNA/DOX nanoparticles. The alginate modification is a useful strategy to improve the calcium carbonate co-precipitation technique for the preparation of gene and drug delivery systems, and the nanoparticles prepared in this study have promising applications in gene and drug delivery.

Concepts and System Design for the Rate-Controlled Drug Delivery Fundamentals of Rate-Controlled Drug Delivery Oral Drug Delivery and Delivery Systems Mucosal Drug Delivery: Potential Routes for Noninvasive Systemic Administration Nasal Drug Delivery and Delivery Systems Ocular Drug Delivery and Delivery Systems Transdermal Drug Delivery and Delivery Systems Parenteral Drug Delivery and Delivery Systems Vaginal Drug Delivery and Delivery Systems Intrauterine Drug Delivery and Delivery Systems Systemic Delivery of Peptide-Based Pharmaceuticals Regulatory Considerations in Controlled Drug Delivery

Drug delivery systems (DDSs) have great potential for improving the treatment of several diseases, especially microbial infections and cancers. However, the formulation procedures of DDSs remain challenging, especially at the nanoscale. Reducing batch-to-batch variation and enhancing production rate are some of the essential requirements for accelerating the translation of DDSs from a small scale to an industrial level. Microfluidic technologies have emerged as an alternative to the conventional bench methods to address these issues. By providing precise control over the fluid flows and rapid mixing, microfluidic systems can be used to fabricate and engineer different types of DDSs with specific properties for efficient delivery of a wide range of drugs and genetic materials. This review discusses the principles of controlled rapid mixing that have been employed in different microfluidic strategies for producing DDSs. Moreover, the impact of the microfluidic device design and parameters on the type and properties of DDS formulations was assessed, and recent applications in drug and gene delivery were also considered.

Cyclodextrin-based self-assembled supramolecular hydrogels and cationic polyrotaxanes for drug and gene delivery applications

Ischemic stroke (IS) ranks as a leading cause of death and disability globally. The blood-brain barrier (BBB) poses significant challenges for effective drug delivery to brain tissues. Recent decades have seen the development of targeted nanomedicine and biomimetic technologies, sparking substantial interest in biomimetic drug delivery systems for treating IS. These systems are devised by utilizing or replicating natural cells and their derivatives, offering promising new pathways for detection and transport across the BBB. Their multifunctionality and high biocompatibility make them effective treatment options for IS. In addition, the incorporation of engineering techniques has provided these biomimetic drug delivery systems with active targeting capabilities, enhancing the accumulation of therapeutic agents in ischemic tissues and specific cell types. This improvement boosts drug transport and therapeutic efficacy. However, it is crucial to thoroughly understand the advantages and limitations of various engineering strategies employed in constructing biomimetic delivery systems. Selecting appropriate construction methods based on the characteristics of the disease is vital to achieving optimal treatment outcomes. This review summarizes recent advancements in three types of engineered biomimetic drug delivery systems, developed from natural cells and their derivatives, for treating IS. It also discusses their effectiveness in application and potential challenges in future clinical translation.

Certain types of cells possess unique characteristics such as tumor homing and prolonged circulation in blood, which are worthy of being exploited in drug delivery carriers for cancer therapy. To improve the delivery efficiency, these cells are integrated with artificial nanocarriers and therapeutic agents to construct biomimetic drug delivery systems. This report provides an overview of recent advances in cell‐derived drug delivery systems for effective cancer treatment. The natural membranes of cells like red blood cells, cancer cells, leukocytes, stem cells, and so on, are extracted and used to form cell membrane–camouflaged nanocarriers, which take advantage of the outstanding biocompatibility and versatile functions of cell membranes. In addition, as an emerging field, biomimetic drug delivery platforms utilizing living cells are also introduced. Finally, the limitations of biomimetic drug delivery systems and the future outlook are discussed and proposed herein.

For progression of health care system, it has always been a challenge to the researchers for formulation to a type of advanced drug delivery system which will have less toxicity, targeted delivery and will be highly biodegradable. Nano science or nanotechnology has been validated to be a successful method as of targeting the drug to its active site be due to its special physicochemical properties and size thereby reducing the dose of administration, increasing bioavailability, and also reducing toxicity. Magnetic nanoparticles recently in few decades have proved as an effective advanced drug delivery system for its elevated magnetic responsiveness, biocompatibility, elevated targeted drug delivery effectiveness, etc. The drug can be easily targeted to active site by application of external magnetic field. Among the various elements, nanoparticles prepared with magnetically active iron oxide or other iron-based spinel oxide nanoparticles are widely used due to its high electrical resistivity, mechanical hardness, chemical stability, etc. Owing to their easy execution towards drug delivery application, extensive research has been carried out in this area. This review paper has summarized all recent modifications of iron-based magnetically active nanoparticle based drug delivery system along with their synthesis, characterization, and applications.

Chapter 11 - Carbon dots as carriers for the development of controlled drug and gene delivery systems

The treatment of infectious diseases and immunizations has experienced a paradigm shift in recent years. With the advent of biotechnology and genetic engineering, not only have various disease-specific biologicals been developed, but an emphasis has also been focused on the effective delivery of such biologicals. The majority of active pharmaceutical ingredients exhibit poor bioavailability, biological degradation, and unexpected underlying adverse effects. To overcome these limitations, developing efficient and new drug delivery systems is crucial in terms of their efficacy across several administration routes, including cutaneous, oral, topical, parenteral, and pulmonary. To accomplish these goals effectively, targeted delivery of drugs/genes to specific tissues/cells has been extensively investigated. The applications of liposomes and niosomes may have advantages over other nanoparticles (NPs) due to their excellent biocompatibility, increased drug loading capacity, and scalability. Liposomes have already gained a significant impact on a number of biomedical fields. They have been proven to be advantageous in stabilizing bioactive components, removing obstacles to cellular and tissue absorption, and optimizing drug biodistribution to target areas in vivo. Encapsulated chemicals are delivered to specific sites while reducing systemic toxicity. Liposomes are promising delivery technologies because of their versatile physicochemical and biophysical properties. Niosomes (nonionic surfactant vesicles), which are being investigated as innovative drug delivery methods, have been shown to enhance the solubility and stability of natural medicinal compounds and other pharmaceutical ingredients. They were developed to facilitate the targeted and controlled release of natural bioactive ingredients. As a result, nanosystems such as liposomes and niosomes have developed into effective methods for enhancing the targeted delivery of drugs and genes. This chapter will provide an overview of the techniques for preparing niosomes and liposomes, the types of niosomes and liposomes, and their characterization and uses in targeted drug and gene delivery systems.KeywordsGenetic engineeringNiosomesLiposomesNanoparticles (NPs)

Advanced drug delivery systems for therapeutic applications.