Medical micro- and nanomotors in the body

Attributed to the miniaturized body size and active mobility, micro- and nanomotors (MNMs) have demonstrated tremendous potential for medical applications. However, from bench to bedside, massive efforts are needed to address critical issues, such as cost-effective fabrication, on-demand integration of multiple functions, biocompatibility, biodegradability, controlled propulsion and in vivo navigation. Herein, we summarize the advances of biomedical MNMs reported in the past two decades, with particular emphasis on the design, fabrication, propulsion, navigation, and the abilities of biological barriers penetration, biosensing, diagnosis, minimally invasive surgery and targeted cargo delivery. Future perspectives and challenges are discussed as well. This review can lay the foundation for the future direction of medical MNMs, pushing one step forward on the road to achieving practical theranostics using MNMs.     

Current aspects of formulation efforts and pore lifetime related to microneedle treatment of skin

Importance of the field: The efficacy of microneedles in the area of transdermal drug delivery is well documented. Multiple studies have shown that enhancement of skin permeation by means of the creation of microscopic pores in the stratum corneum can greatly improve the delivery rates of drugs. However, skin pretreatment with microneedles is not the only factor affecting drug transport rates. Other factors, including drug formulation and rate of micropore closure, are also important for optimizing delivery by this route.

Areas covered in this review: This review aims to highlight work that has been done in these areas, with an emphasis on drug formulation parameters that affect transdermal flux.

What the reader will gain: This review creates an appreciation for the many factors affecting microneedle-enhanced delivery. Most results clearly indicate that microneedle skin pretreatment by itself may have different effects on drug transport depending on the formulation used, and formulation characteristics have different effects on the transport through untreated skin and microneedle-treated skin. Several formulation approaches are reported to optimize microneedle-enhanced drug delivery, including co-solvent use, vesicular, nanoparticulate and gel systems.

Take home message: In addition to well-established factors that affect microneedle-assisted delivery (geometry, type of microneedle, etc.), formulation and pore viability are also critical factors that must be considered.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.     

Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems

Importance of the field: The advancement in material design and engineering has led to the rapid development of new materials with increasing complexity and functions. Both non-degradable and degradable polymers have found wide applications in the controlled delivery field. Studies on drug release kinetics provide important information into the function of material systems. To elucidate the detailed transport mechanism and the structure-function relationship of a material system, it is critical to bridge the gap between the macroscopic data and the transport behavior at the molecular level.

Areas covered in this review: The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literature published after the 1990s. The release kinetics of selected drug compounds from various material systems is discussed in case studies. Recent progress in the mathematical models based on different transport mechanisms is highlighted.

What the reader will gain: This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices.

Take home message: Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Moreover, developing complex polymeric matrices requires more robust mathematical models to elucidate the solute transport mechanisms.     

Cell-mediated drug delivery

Introduction: Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus, immune cells can be exploited as Trojan horses for drug delivery.

Areas covered: This paper reviews how immunocytes laden with drugs can cross the blood–brain or blood–tumor barriers to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points.

Expert opinion: Using cells as delivery vehicles enables targeted drug transport and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a new disease-combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms in drug delivery may open new perspectives for the active delivery of drugs.     

Liposomes for brain delivery

Introduction: Development of drug delivery systems for brain delivery is one of the most challenging research topics in pharmaceutical areas, mainly due to the presence of the blood–brain barrier (BBB), which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the majority of therapeutic agents. Among the several carriers, which have been studied to overcome this problem, liposomes have gained increasing attention as promising strategies for brain-targeted drug delivery. The most advantageous features of liposomes are their ability to incorporate and deliver large amounts of drug and the possibility to decorate their surface with different ligands.

Areas covered: The purpose of this review is to explore the different approaches studied to transport and deliver therapeutics and imaging agents to the brain by using liposomes. In the first part of the review, particular attention is paid to describe the anatomy of the BBB and different physiological transport mechanisms available for drug permeation. In the second part, the different strategies for the delivery of a drug to the brain using liposomes are reviewed for each transport mechanism.

Expert opinion: Over the last decade, there have been significant developments concerning liposomal brain delivery systems conjugated with selected ligands with high specificity and low immunogenicity. An universally useful liposomal formulation for brain targeting does not exist but liposome design must be modulated by the appropriate choice of the specific homing device and transport mechanism.     

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier: an excellent platform for brain targeting

Introduction: The blood–brain barrier (BBB) represents a stringent barrier for delivery of neurotherapeutics in vivo. An attempt to overcome this barrier is represented by the direct transport of drugs from the nose to the brain along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain. An enormous range of neurotherapeutics, both macromolecules and low molecular weight drugs, can be delivered to the central nervous system (CNS) via this route.

Areas covered: Present review highlights the literature on the anatomy-physiology of the nasal cavity, pathways and mechanisms of neurotherapeutic transport across nasal epithelium and their biofate and various strategies to enhance direct nose to brain drug delivery. The authors also emphasize a variety of drug molecules and carrier systems delivered via this route for treating CNS disorders. Patents related to direct nose to brain drug delivery systems have also been listed.

Expert opinion: Direct nose to brain drug delivery system is a practical, safe, non-invasive and convenient form of formulation strategy and could be viewed as an excellent alternative approach to conventional dosage forms. Existence of a direct transport route from the nasal cavity to the brain, bypassing the BBB, would offer an exciting mode of delivering neurotherapeutic agents.     

Drug delivery systems for differential release in combination therapy

Introduction: Combination therapy with multiple therapeutic agents has wide applicability in medical and surgical treatment, especially in the treatment of cancer. Thus, new drug delivery systems that can differentially release two or more drugs are desired. Utilizing new techniques to engineer the established drug delivery systems and synthesizing new materials and designing carriers with new structures are feasible ways to fabricate proper multi-agent delivery systems, which are critical to meet requirements in the clinic and improve therapeutic efficacy.

Areas covered: This paper aims to give an overview about the multi-agent delivery systems developed in the last decade for differential release in combination therapy. Multi-agent delivery systems from nanoscale to bulk scale, such as liposomes, micelles, polymer conjugates, nano/micorparticles and hydrogels, developed over the last 10 years, have been collected and summarized. The characteristics of different delivery systems are described and discussed, including the structure of drug carriers, drug-loading techniques, release behaviors and consequent evaluation in biological assays.

Expert opinion: The chemical structure of drug delivery systems is the key to controlling the release of therapeutic agents in combination therapy, and the differential release of multiple drugs could be realized by the successful design of a proper delivery system. Besides biological evaluation in vitro and in vivo, it is important to speed up practical application of the resulting delivery systems.     

Nasal route: an alternative approach for antiemetic drug delivery

Introduction: Antiemetic drugs are used in the treatment of nausea and emesis. Development of novel delivery systems for antiemetic drugs, as an alternative to conventional preparations, is important in terms of good patient compliance and improving bioavailability. The nasal route offers unique superiorities, such as fast and high drug absorption, and high patient compliance. Therefore, a considerable amount of research has been carried out on the development of nasal delivery systems for antiemetic drugs.

Areas covered: This review deals with the importance of nasal delivery of antiemetic drugs and the studies performed on this subject. The first part of this review summarizes the properties of the nasal route, its advantages and limitations, parameters affecting drug absorption through nasal mucosa, nasal passage pathways and general approaches to improve nasal transport. The second part reviews the studies conducted on the development of nasal delivery systems.

Expert opinion: Due to its superiorities, the nasal route could be considered as an attractive alternative to oral and parenteral routes. To overcome the barrier properties of the nasal epithelium and to enhance transport of antiemetic drugs, several approaches, including permeation enhancers, in situ gel formulations and micro- and nanoparticulate systems, have been evaluated. The results obtained are promising and indicate that nasal formulations of some antiemetic drugs may enter the market in the near future.     

Erythrocytes-based synthetic delivery systems: transition from conventional to novel engineering strategies

Introduction: Erythrocytes (red blood cells [RBCs]) and artificial or synthetic delivery systems such as liposomes, nanoparticles (NPs) are the most investigated carrier systems. Herein, progress made from conventional approach of using RBC as delivery systems to novel approach of using synthetic delivery systems based on RBC properties will be reviewed.

Areas covered: We aim to highlight both conventional and novel approaches of using RBCs as potential carrier system. Conventional approaches which include two main strategies are: i) directly loading therapeutic moieties in RBCs; and ii) coupling them with RBCs whereas novel approaches exploit structural, mechanical and biological properties of RBCs to design synthetic delivery systems through various engineering strategies. Initial attempts included coupling of antibodies to liposomes to specifically target RBCs. Knowledge obtained from several studies led to the development of RBC membrane derived liposomes (nanoerythrosomes), inspiring future application of RBC or its structural features in other attractive delivery systems (hydrogels, filomicelles, microcapsules, micro- and NPs) for even greater potential.

Expert opinion: In conclusion, this review dwells upon comparative analysis of various conventional and novel engineering strategies in developing RBC based drug delivery systems, diversifying their applications in arena of drug delivery. Regardless of the challenges in front of us, RBC based delivery systems offer an exciting approach of exploiting biological entities in a multitude of medical applications.     

Gateways for the intracellular access of nanocarriers: a review of receptor-mediated endocytosis mechanisms and of strategies in receptor targeting

Importance of the field: The last 10 years have seen a dramatic growth in understanding and controlling how complex, drug-loaded (nano)structures, as well as pathogens, or biopharmaceuticals can gather access to the cytoplasm, which is a key step to increasing the effectiveness of their action.

Areas covered in this review: The review offers an updated overview of the current knowledge of endocytic processes; furthermore, the cell surface receptors most commonly used in drug delivery are here discussed on the basis of their reported internalization mechanisms, with examples of their use as nanocarrier targets taken from the most recent scientific literature.

What the reader will gain: Knowledge of molecular biology details is increasingly necessary for a rational design of drug delivery systems. Here, the aim is to provide the reader with an attempt to link a mechanistic knowledge of endocytic mechanisms with the identification of appropriate targets (internalization receptors) for nanocarriers.

Take home message: Much advance is still needed to create a complete and coherent biological picture of endocytosis, but current knowledge already allows individuation of a good number of targetable groups for a predetermined intracellular fate of nanocarriers.     

Drug delivery using multifunctional dendrimers and hyperbranched polymers

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems.

Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining high loading of active ingredients coupled with controlled and/or triggered release.

What the reader will gain: Readers will be exposed to the strategy of synthesizing multifunctional polymers, aimed at the development of effective drug delivery systems.

Take home message: Multifunctional systems upgrade the therapeutic potential of drugs and, in certain cases, may even lead to the application of new bioactive compounds that would otherwise not be feasible.     

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.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

Introduction: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems.

Areas covered: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems.

Expert opinion: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.     

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.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

Drug Delivery and Transport to Solid Tumors

Purpose. The purpose of this review is to provide an overview of the principles of and barriers to drug transport and delivery to solid tumors. Methods. This review consists of four parts. Part I provides an overview of the differences in the vasculature in normal and tumor tissues, and the relationship between tumor vasculature and drug transport. Part II describes the determinants of transport of drugs and particles across tumor vasculature into surrounding tumor tissues. Part III discusses the determinants and barriers of drug transport, accumulation, and retention in tumors. Part IV summarizes the experimental approaches used to enhance drug delivery and transport in solid tumors. Results. Drug delivery to solid tumors consists of multiple processes, including transport via blood vessels, transvascular transport, and transport through interstitial spaces. These processes are dynamic and change with time and tumor properties and are affected by multiple physicochemical factors of a drug, multiple tumor biologic factors, and as a consequence of drug treatments. The biologic factors, in turn, have opposing effects on one or more processes in the delivery of drugs to solid tumors. Conclusion. The effectiveness of cancer therapy depends in part on adequate delivery of the therapeutic agents to tumor cells. A better understanding of the processes and contribution of these factors governing drug delivery may lead to new cancer therapeutic strategies.     

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.     

An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part II

Introduction: Interest in hot-melt extrusion (HME) technology for novel applications is growing day by day, which is evident from several hundred publications within the last 5 years. HME is a cost-effective, solvent free, ‘green’ technology utilized for various formulations with low investment costs compared to conventional technologies. HME has also earned the attention of the pharmaceutical industry by the transformation of this technology for application in continuous manufacturing.

Areas covered: Part II of the review focuses on various novel opportunities or innovations of HME such as multiple component systems (co-crystals, co-amorphous systems and salts), twin-screw granulation, semi-solids, co-extrusion, abuse deterrent formulations, solid self-emulsifying drug delivery systems, chronotherapeutic drug delivery systems, and miscellaneous applications.

Expert opinion: HME is being investigated as an alternative technology for preparation of multicomponent systems such as co-crystals and co-amorphous techniques. Twin-screw granulation has gained increased interest in preparation of granules via twin-screw melt granulation or twin-screw dry granulation. This novel application of the HME process provides a promising alternate approach in the formulation of granules and solid dosage forms. However, this technology may need to be further investigated for scalability aspects of these novel applications for industrial production.