Simulation-based approaches for drug delivery systems: Navigating advancements, opportunities, and challenges

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.

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

Crossing Barriers From blood-to-brain and academia-to-industry

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.

Nanohybrid cerasomes: Advancements in targeted drug and gene delivery

The development of an efficient and innovative drug delivery system is essential to improve the pharmacological parameters of the medicinal compound or drug. The technique or manner used to improve the pharmacological parameters plays a crucial role in the delivery system. In the current scenario, various drug delivery systems are available where nanotechnology has firmly established itself in the field of drug delivery. One of the most prevalent elements is carbon with its allotropic modifications such as graphene-based nanomaterials, carbon nanotubes, carbon dots, and carbon fullerenes, these nanomaterials offer notable physiochemical and biochemical properties for the delivery applications due to their smaller size, surface area, and ability to interact with the cells or tissues. The exceptional physicochemical properties of carbon-based 2D nanomaterials, such as graphene and carbon nanotubes, make them attractive candidates for drug delivery systems. These nanomaterials offer a large surface area, high drug loading capacity, and tunable surface chemistry, enabling efficient encapsulation, controlled release, and targeted delivery of therapeutic agents. These properties of the nanomaterials can be exploited for drug delivery applications, like assisting the target delivery of drugs and aiding combination molecular imaging. This review emphasizes on the recent patents on 2D carbon-based nanomaterial and their role in drug delivery systems. Carbon-based 2D nanomaterials present a wealth of opportunities for advanced drug delivery systems. Their exceptional properties and versatility offers great potential in improving therapeutic efficacy, minimizing side effects, and enabling personalized medicine and the recent patents on 2D nanomaterial.

Some cancers such as human breast cancer, prostate cancer, and lung cancer easily metastasize to bone, leading to osteolysis and bone destruction accompanied by a complicated microenvironment. Systemic administration of bisphosphonates (BP) or denosumab is the routine therapy for osteolysis but with non-negligible side effects such as mandibular osteonecrosis and hypocalcemia. Thus, it is imperative to exploit optimized drug delivery systems, and some novel nanotechnology and nanomaterials have opened new horizons for scientists. Targeted and local drug delivery systems can optimize biodistribution depending on nanoparticles (NPs) or microspheres (MS) and implantable biomaterials with the controllable property. Drug delivery kinetics can be optimized by smart and sustained/local drug delivery systems for responsive delivery and sustained delivery. These delicately fabricated drug delivery systems with special matrix, structure, morphology, and modification can minimize unexpected toxicity caused by systemic delivery and achieve desired effects through integrating multiple drugs or multiple functions. This review summarized recent studies about optimized drug delivery systems for the treatment of cancer metastatic osteolysis, aimed at giving some inspiration in designing efficient multifunctional drug delivery systems.

Advancements and challenges in carbon nanotube-based drug delivery systems

Numerous approaches have been employed to improve the efficacy of drug and gene delivery systems, but their strategic development is hindered by a lack of mechanistic understanding and assessment of drug transport and action. Optimizing the efficiency of a drug delivery system requires a detailed understanding of the pharmacokinetics, transendothelial transport, distribution at the tumor site, and uptake in target cells. Elucidating transport kinetics and rate-limiting steps in animal models can be extremely challenging, while in vitro platforms often fail to recapitulate the complexities of drug transport in vivo. To recapitulate the critical aspects of delivery of anticancer agents, we have developed a 3D tissue-engineered microvessel model of the tumor microenvironment. Our model consists of single MDA-MB-231 breast cancer cells embedded within a collagen matrix that surrounds a perfusable cylindrical microvessel lined with human endothelial cells. Here we compare transport and action of free doxorubicin and Doxil, a liposomal formulation of doxorubicin. We show that the mode of drug delivery influences uptake in the vessel endothelium and tumor cells. Through quantification of endothelial and tumor cell proliferation, apoptosis, and motility, we profile the kinetics of drug action with mechanisms of drug transport across the vessel lumen and into the surrounding matrix. Our model can be customized to mimic specific tumor microenvironments and disease states within a physiologically relevant microfluidic platform and provides a basis for characterizing and optimizing drug delivery systems.

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

Considerable research exercises have been directed towards the development of efficient and safe drug delivery systems. Various materials are used in different pharmaceutical formulations for the development of efficient drug delivery systems in the treatment of disease. Biopolymers are a choice of research as an excipient delivery system due to their biodegradability, low toxicity, safe, stable, and renewable nature. Biopolymers are naturally occurring polymers or polymer matrix composites, that are extracted from animals, bacteria, fungi, and plants. Cellulose, starches are carbohydrate-based polymers, and wool, silk, gelatin, and collagen are protein-based biopolymers. Biopolymers are obtained from various sources but biopolymers, that belong to the carbohydrate origin, have been found very promising in drug delivery through various routes. The review mainly focuses on the biopolymers currently in use for buccal-mediated pharmaceutical drug delivery systems because the buccal route is an efficient drug delivery system that allows direct systemic circulation of drugs. It also prevents the hydrolysis of the drug molecule in the gastrointestinal tract and thus increases the bioavailability of the drug. The present review discusses the overview of other drug delivery routes, challenges with conventional drug delivery systems, pharmaceutical applications of some biopolymers used in buccal drug delivery systems, that are published recently, currently in use, or used over the past decade.

Проведено огляд літературних джерел щодо розробки та дослідження осмотичних систем вивільнення та доставки лікарських речовин

Editorial

Part I: Pharmacological Considerations for Drug Delivery Systems in Cancer Medicine Systemically Administered Drugs Reginald B. Ewesuedo and Mark J. Ratain Regional Administration of Antineoplastic Drugs Maurie Markman Theoretical Analyses and Simulations of Anticancer Drug Delivery Ardith W. El-Kareh and Timothy W. Secomb Part II: Technologies Available for Use in Cancer Drug Delivery Systems Biopolymers for Parenteral Drug Delivery in Cancer Treatment Wolfgang Friess Hydrogels in Cancer Drug Delivery Systems Sung-Joo Hwang, Namjin Baek, Haesun Park, and Kinam Park Microparticle Drug Delivery Systems Duane T. Birnbaum and Lisa Brannon-Peppas Polyethylene Glycol Conjugation of Protein and Small Molecule Drugs: Past, Present, and Future Robert G. L. Shorr, Michael Bentley, Simon Zhsao, Richard Parker, and Brendan Whittle Emulsions As Anticancer Delivery Systems S. Esmail Tabibi Part III. Current Applications: Products Approved or in Advanced Clinical Development Liposomal Drug Delivery Systems for Cancer Therapy Daryl C. Drummond, Dmitri Kirpotin, Christopher C. Benz, John W. Park, and Keelung Hong Gliadel(R): A New Method for the Treatment of Malignant Brain Tumors Francesco DiMeco, Henry Brem, Jon D. Weingart, and Alessandro Olivi Intralesional Chemotherapy with Injectable Collagen Gel Formulations Elaine K. Orenberg Sustained-Release Drug Delivery with DepoFoam Sankaram B. Mantripragada and Stephen B. Howell Cancer Vaccines Susanne Osanto Part IV. Future Directions: Novel Cancer Drug Targets and Delivery Systems Gene Therapy of Cancer Susanne Osanto Progress in Antisense Technology Stanley T. Crooke Tumor Vaccines Francesco M. Marincola Diagnosis and Treatment of HumanDisease Using Telomerase As a Novel Target Lynne W. Elmore and Shawn E. Holt Index

Design and synthesis of well-ordered drug delivery systems are very important for medicinal and pharmaceutical and health care. Innovations of materials through nanotechnology and hydrogels have synergistically energized the growth of drug delivery. Uniqueness in material chemistry permits the creation of environmentally approachable, biocompatible, biodegradable and targeted drug delivery system. Large numbers of biopolymers have been examined for the design of drug delivery systems. Structure, size, shape and multi-functionality of drug delivery system can be controlled by the nanotechnology combined with biopolymer. Hydrogels have also been investigated as smart delivery systems capable to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. This review mainly focuses on drug delivery applications of nanoparticles modified biopolymers and effective drug delivery system of biopolymer network based on hydrogels.