The advancing uses of nano-graphene in drug delivery

Introduction: Graphene has been received with great interest in various fields including biomedical applications. Due to its ultrahigh surface area and easy surface functionalization, single-layered graphene has been intensively explored for drug and gene delivery. Utilizing their intrinsic high near-infrared absorbance, graphene and its derivatives have been found to be excellent candidates for multimodal imaging guided combined cancer photothermal and chemo- and/or photodynamic therapies.

Areas covered: This review summarizes recent studies on the biomedical applications of various graphene-based nanomaterials. The authors provide a comprehensive summary on using properly functionalized nano-graphene and its derivatives for drug and gene delivery, as well as combination therapy of cancer.

Expert opinion: Regarding biomedical applications, the authors find that proper surface functionalization and controlled sizes of graphene-based nanomaterials are two crucial factors for efficient drug and gene delivery. Although a lot of work has demonstrated the successful delivery of anticancer drugs and genes using graphene-based nanomaterials as carriers, the correlations of their surface functionalization and size distribution and their therapeutic outcomes need more exploration. On the other hand, the long-term toxicological and metabolic behaviors of nano-graphene still merit significantly more effort before clinical use.     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.     

Polymeric networks for controlled release of drugs: a patent review

Introduction: Polymeric networks for controlled drug delivery possess wide pharmaceutical and biomedical applications.

Areas Covered: In this review, we explore the diversity of polymeric networks that exist, from simple to highly complex and ‘smart’ embodiments. The patented delivery systems reviewed reflect this, based on both conventional polymeric networks and stimulus-responsive networks where engineering of a controlled molecular architecture of polymeric networks enables a defined response to external or internal stimuli. Future trends in terms of nano-sized polymeric network patents are also highlighted.

Expert Opinion: A critical analysis of challenges potentially facing extended propulsion of the research and development of polymeric networks is provided. The significant therapeutic potential of polymer networks for controlled drug delivery is highlighted in the patented drug delivery systems examined; however, there needs to be enhanced representation of such systems in the market and thus available to patients. Concerted efforts are therefore necessary to propel these systems from the experimental setting to pilot scale production, and preclinical and clinical testing, for extension of their practicality.     

Recent advances in cyclodextrin delivery techniques

Introduction: Active pharmaceutical ingredients (APIs) are evolving from low-molecular-weight drugs to peptide-, protein-, gene-, oligonucleotide- and cell-based drugs. Therefore, advanced pharmaceutical technologies are required to achieve manifestation of the drug efficacy, side effect reduction and the adequate dosage form design.

Areas covered: In this review, the authors highlight the recent advances in drug delivery techniques utilizing cyclodextrins (CyDs), and cyclic oligosaccharides consisting of α-1,4-linked α-D-glucopyranose units, for various drugs described above. Especially, drug delivery system consisting of combination systems of CyDs and functional materials such as dendrimer, liposome and PEG are introduced. Furthermore, the utilities of CyDs as APIs have been also described.

Expert opinion: To achieve the controlled release and/or targeting of low-molecular-weight drugs in systemic administration, the construction of novel CyDs and CyD the supramolecular system should be a useful approach because of the stable complexation of drugs with CyDs. In addition, the combination systems of CyDs and various carriers have the potential as advanced drug delivery systems for proteins and nucleic acids. Furthermore, CyDs have great potential as APIs for various diseases with few side effects, although the detailed mechanism, especially cellular uptake of CyDs, should be clarified.     

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Introduction: Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure–function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release.

Areas covered: An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence–structure–function relationships, stimuli-responsive features and current and potential drug delivery applications.

Expert opinion: The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Drug delivery by red blood cells: vascular carriers designed by mother nature

Importance of the field: Vascular delivery of several classes of therapeutic agents may benefit from carriage by red blood cells (RBC), for example, drugs that require delivery into phagocytic cells and those that must act within the vascular lumen. The fact that several protocols of infusion of RBC-encapsulated drugs are now being explored in patients illustrates a high biomedical importance for the field.

Areas covered by this review: Two strategies for RBC drug delivery are discussed: encapsulation into isolated RBC ex vivo followed by infusion in compatible recipients and coupling therapeutics to the surface of RBC. Studies of pharmacokinetics and effects in animal models and in human studies of diverse therapeutic enzymes, antibiotics and other drugs encapsulated in RBC are described and critically analyzed. Coupling to RBC surface of compounds regulating immune response and complement, affinity ligands, polyethylene glycol alleviating immune response to donor RBC and fibrinolytic plasminogen activators are described. Also described is a new, translation-prone approach for RBC drug delivery by injection of therapeutics conjugated with fragments of antibodies providing safe anchoring of cargoes to circulating RBC, without need for ex vivo modification and infusion of RBC.

What the reader will gain: Readers will gain historical perspective, current status, challenges and perspectives of medical applications of RBC for drug delivery.

Take home message: RBC represent naturally designed carriers for intravascular drug delivery, characterized by unique longevity in the bloodstream, biocompatibility and safe physiological mechanisms for metabolism. New approaches for encapsulating drugs into RBC and coupling to RBC surface provide promising avenues for safe and widely useful improvement of drug delivery in the vascular system.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Hydrogels with smart systems for delivery of hydrophobic drugs

Introduction: Smart hydrogel systems present opportunities to not only provide hydrophobic molecule encapsulation capability but to also respond to specific delivery routes.

Areas covered: An overview of the design principles, preparation methods and applications of hydrogel systems for delivery of hydrophobic drugs is given. It begins with a summary of the advantages of hydrogels as delivery vehicles over other approaches, particularly macromolecular nanocarriers, before proceeding to address the design and preparation strategies and chemistry involved, with a particular focus on the introduction of hydrophobic domains into (naturally) hydrophilic hydrogels. Finally, the applications in different delivery routes are discussed.

Expert opinion: Modifications to conventional hydrogels can endow them with the capability to carry hydrophobic drugs but other functions as well, such as the improved mechanical stability, which is important for long-term in vivo residence and/or self-healing properties useful for injectable delivery pathways. These modifications harness hydrophobic-hydrophobic forces, physical interactions and inclusion complexes. The lack of in-depth understanding of these interactions, currently limits more delicate and application-oriented designs. Increased efforts are needed in (i) understanding the interplay of gel formation and simultaneous drug loading; (ii) improving hydrogel systems with respect to their biosafety; and (iii) control over release mechanism and profile.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Zinc-based metal–organic frameworks as nontoxic and biodegradable platforms for biomedical applications: review study

Abstract

Development of biomedical systems for controllable drug delivery systems and construction of biosensors is imperative to reduce side effects of common treatment techniques and enhance the therapeutic efficacy. To address this issue, metal–organic frameworks (MOFs) as hybrid porous polymeric structures have attracted worldwide attention due to their unprecedented opportunities in vast range of applications in diverse fields including chemistry, biological, and medicinal science as gas storage/separation, sensing, and drug delivery systems. Recently, biomedical application has become an interesting and promising issue for development and usage of multi-functional MOFs. Flexible chemical composition and versatile porous structure of MOFs enable the engineering and enhancement of their medical formulation and functionality as practical carriers for whether therapeutic or imaging agents. One important point in this domain is the efficient delivery of drugs in the body using nontoxic and biodegradable carriers. This review brings together the literatures that addressing the biomedical applications of Zinc-based MOFs (i.e. as drug delivery systems or nontoxic agent in matter of therapeutic applications) to present recent achievements in this interesting field.     

Innovations in bioadhesive vaginal drug delivery system

Introduction: Vagina, due to its anatomical position and physiological characteristics is increasingly being explored as a site for drug delivery in recent years. This route coupled with bioadhesion phenomena has born fruitful results in delivering drugs both locally as well as systemically.

Areas covered: Bioadhesive vaginal drug delivery system has been used for the treatment of local diseases affecting the vagina like candidiasis, STD, vaginal dryness, and so on. Also, research has demonstrated that drugs can be successfully delivered to systemic circulation via vaginal mucosa for treatment of various diseases like migraine and osteoporosis. Besides, this vaginal route has also been used for uterine targeting of drugs. This review focuses on these recent innovations that have been patented in the area of bioadhesive vaginal drug delivery systems. The review also highlights certain physicochemical characteristics of bioadhesive polymers that affect drug delivery through this route.

Expert opinion: An in-depth study of this review will give an insight into the potential areas that can be explored while designing a bioadhesive vaginal drug delivery system. Also, the in vitro and in vivo experimental results discussed in the review will help stimulate research in development and optimization of newer formulations.     

The alluring potential of functionalized carbon nanotubes in drug discovery

Importance of the field: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses.

Areas covered in this review: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy.

What the reader will gain: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed.

Take home message: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining – and in some cases improving – their therapeutic efficacy.     

Patented pulsatile drug delivery technologies for chronotherapy

Introduction: Oral-controlled and modified-release drug delivery systems with zero-order sustained-release kinetics have been developed and proven suitable for meeting increasingly sophisticated therapeutic needs. Nevertheless, the impact of basic chronobiology concepts on the practice of medicine is still ongoing and to address chronotherapy needs, various types of pulsatile drug delivery systems have been innovated. The purpose of this review is to highlight these innovations in the field of chronotherapy.

Areas covered: The present review discusses in depth on recent patents and developments related to pulsatile drug delivery systems with eroding, soluble or rupturable barrier coatings, and systems with capsular structures. Besides focusing on all recent innovations, the review addresses the novelty and feasibility of all upcoming technologies being exploited considering pulsatile drug delivery systems.

Expert opinion: There has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable and well-defined lag phase from the time of administration. From 1981 until the present date, patent publications related to pulsatile drug delivery have shown more promising systems with numerous developments in arena of drug delivery. Future development of chronotherapeutic medications requires proper assessment and integration with other emerging disciplines such as hydrogel and transdermal delivery systems. The selection of the appropriate chronopharmaceutical technology should take into considerations with the ease of manufacturing and the cost-effectiveness.     

Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery

Introduction: Aptamers are short, single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. These properties, as well as rapid tissue penetration and ease of chemical modification, make aptamers ideal recognition elements for in vivo targeted drug delivery and attractive molecules for use in disease diagnosis and therapy.

Areas covered: The general properties of aptamers as well as advantages over their counterpart antibodies are briefly discussed. Next, aptamer selection by cell- systematic evolution of ligands by exponential enrichment is described in detail. Finally, the review summarizes recent progress in the field of targeted drug delivery based on aptamers and their conjugation to liposomes, micelles and other nanomaterials.

Expert opinion: Advances in nanotechnology have led to new and improved nanomaterials for biomedical applications. Conjugation of nanoparticles (NPs) with aptamers exploits both technologies, making aptamer-NP conjugates ideal agents for drug delivery with proven therapeutic effects and the reduction of toxicity to normal tissue. The use of multivalent aptamer-conjugated nanomaterials represents one of the new directions for drug development in the future; as such, continuing studies of these multivalent aptamers and bioconjugates should result in important clinical applications in targeted drug delivery.     

Polyacrylic acid polymers hydrogels intended to topical drug delivery: preparation and characterization

Abstract

Context: Bioadhesiviness of polyacrylic acid polymers make them promising hydrogels to design topical drug delivery systems, allowing a close contact with biological substrate as well as an enhanced local concentration gradient, both factors that may improve the biological performance of the drugs.

Aim: Texture and bioadhesive properties of hydrogels were assessed by using texture analyzer and they were correlated with their rheological behavior and performance as drug delivery systems.

Methods: Aqueous dispersions of both polymers were prepared at 0.5%, 1.0% and 1.5% w/v. Hardness, compressibility, adhesiveness, cohesiveness, bioadhesion, continuous flow, oscillatory dynamic test and in vitro drug release were evaluated.

Results: Rheological and texture parameters were dependent on polymer concentration and C974P polymer built the strongest structures. Both 1.5% hydrogels presented high bioadhesion values. About 50% of the metronidazole (MTZ) was sustained released from hydrogels within 2?h with an initial burst release at early stage. After, the release rates were decreased and 10% of the MTZ was released in the next 10?h. The drug release process was driven by Fickian diffusion and complex mechanism for PP and C974P hydrogels, respectively.

Conclusion: The set of results demonstrated that these hydrogels are promising to be used as topical controlled drug delivery system.     

Chitosan-based gastroretentive floating drug delivery technology: an updated review

Introduction: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care.

Areas covered: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed.

Expert opinion: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future.     

Drug delivery/imaging multifunctionality of mesoporous silica-based composite nanostructures

Introduction: Biocompatible mesoporous silica nanoparticles (MSNs) are regarded as one of the most promising inorganic drug delivery systems (DDSs) to concurrently enhance the therapeutic efficiency and mitigate the side effects of anticancer drugs. Elaborately combining multicomponents with MSNs will endow them with specific functionalities for cancer therapy and diagnosis, such as targeted drug delivery, intelligent on-demand drug releasing, synergistic therapy, diagnostic imaging and so on.

Areas covered: This review discusses the state-of-the-art potential obstacles and further perspectives of the chemical design/synthesis, in vitro/in vivo pharmaceutical evaluations and potential clinical translations of multifunctional mesoporous silica-based nanomaterials for biotechnological and biomedical applications, especially against cancer. These topics cover the years from 2001 to 2013.

Expert opinion: Through the comprehensive evaluations of the biosafety and pharmaceutical efficiency, elaborately designed/fabricated mesoporous silica-based composite nanoparticles show great potentials in clinical applications for efficient diagnostic imaging and chemotherapy of cancer.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.