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.     

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent.

Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry.

Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.     

Liposomes as delivery systems for nasal vaccination: strategies and outcomes

Importance of the field: Among the particulate systems that have been envisaged in vaccine delivery, liposomes are very attractive. These phospholipid vesicles can indeed deliver a wide range of molecules. They have been shown to enhance considerably the immunogenicity of weak protein antigens or synthetic peptides. Also, they offer a wide range of pharmaceutical options for the design of vaccines. In the past decade, the nasal mucosa has emerged as an effective route for vaccine delivery, together with the opportunity to develop non-invasive approaches in vaccination.

Areas covered in this review: This review focuses on the recent strategies and outcomes that have been developed around the use of liposomes in nasal vaccination.

What the reader will gain: The various formulation parameters, including lipid composition, size, charge and mucoadhesiveness, that have been investigated in the design of liposomal vaccine candidates dedicated to nasal vaccination are outlined. Also, an overview of the immunological and protective responses obtained with the developed formulations is presented.

Take home message: This review illustrates the high potential of liposomes as nasal vaccine delivery systems.     

Nanostructured hyaluronic acid-based materials for active delivery to cancer

Importance of the field: Active targeting of bioactive molecules by physicochemical association with hyaluronic acid (HA) is an attractive approach in current nanomedicine because HA is biocompatible, non-toxic and non-inflammatory.

Areas covered in this review: This review focuses on synthesis, physicochemical characterization and biological properties of different nanoparticulate delivery systems that include HA in their structures. Chemically based approaches to the delivery of small molecule drugs, proteins and nucleic acids in which they become chemically or physically bound to hyaluronic acid are reviewed, including the use of molecular HA conjugates and nanocarriers. The systems are considered in terms of intracellular delivery to different cultured cells that express HA-specific receptors (hyaladherines) differently. The in vivo biodistribution and therapeutic effect of these systems are discussed.

What the reader will gain: Different synthetic methodologies for preparations of HA-based nanoparticles are presented extensively. HA nanoparticulate systems of various structures can be compared with respect to their in vitro assays and in vivo biodistribution.

Take home message: To make HA useful as an intravenous targeting carrier, strategies have to be devised to: reduce HA clearance from the blood; suppress the HA uptake by liver and spleen; and provide tumor-triggered mechanisms of release of an active drug from the HA carrier.     

Liposomes in cosmeceutics

Introduction: Cosmeceuticals are cosmetic products with biologically active ingredients purporting to have medical or drug-like benefits. Some cosmeceuticals can act effectively when reaching their target sites in the deeper layers of the skin. However, the barrier nature of skin causes significant difficulties for compounds to be delivered through. Therefore, scientists are investigating various strategies to overcome these barrier properties. Liposomes have been claimed to improve the topical delivery of compounds.

Areas covered: This paper offers a brief overview of current approaches in the research and development of liposomal formulations to improve the performance of cosmeceuticals, from recent literature. This review deals with the potential of liposomes as a skin delivery system for cosmeceuticals, with a focus on the clinical application of liposomes.

Expert opinion: Liposomes are well-known vesicular cosmetic delivery systems. The topical application of liposomes offers a wide range of advantages including increased moisturization, restoring action, biodegradability, biocompatibility and extended and slow dermal release. Their similar structure to biological membranes allows penetration into the epidermal barrier, compared with other delivery systems. The incorporation of cosmeceuticals using suitable delivery systems is important in the management of cosmetic disorders.     

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.     

Applications of nanoparticles in cancer medicine and beyond: optical and multimodal in vivo imaging,tissue targeting and drug delivery

Introduction: Nanotechnology has opened up the way to the engineering of new organized materials endowed with improved performances. In the past decade, engineered nanoparticles (NPs) have been progressively implemented by exploiting synthetic strategies that yield complex materials capable of performing functions with applications also in medicine. Indeed, in the field of ‘nanomedicine’ it has been explored the possibility to design multifunctional nanosystems, characterized by high analytical performances and stability, low toxicity and specificity towards a given cell target.

Area covered: In this review article, we summarize the advances in the engineering of NPs for biomedical applications, from optical imaging (OI) to multimodal OI and targeted drug delivery. For this purpose, we will provide some examples of how investigations in nanomedicine can support preclinical and clinical research generating innovative diagnostic and therapeutic strategies in oncology.

Expert opinion: The progressive breakthroughs in nanomedicine have supported the development of multifunctional and multimodal NPs. In particular, NPs are significantly impacting the diagnostic and therapeutic strategies since they allow the development of: NP-based OI probes containing more than one modality-specific contrast agent; surface functionalized NPs for specific ‘molecular recognition’. Therefore, the design and characterization of innovative NP-based systems/devices have great applicative potential into the medical field.     

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.     

Nanoparticles for human liver-specific drug and gene delivery systems: in vitro and in vivo advances

A wide variety of nanoparticles (NPs) that can deliver incorporated therapeutic materials such as compounds, proteins, genes and siRNAs to the human liver have been developed to treat liver-related diseases. This review describes NP-based drug and gene delivery systems such as liposomes (including lipoplex), polymer micelles, polymers (including polyplex) and viral vectors. It focuses upon the modification of these NPs to enhance liver specificity or delivery efficiency in vitro and in vivo. We discuss recent advances in drug and gene delivery systems specific to the human liver utilizing bio-nanocapsules comprising hepatitis B virus (HBV) envelope L protein, which has a pivotal role in HBV infection. These NP-based medicines may offer novel strategies for the treatment of liver-related diseases and contribute to the development of nanomedicines targeting other tissues.     

Recent advances of siRNA delivery by nanoparticles

Introduction: The field of RNA interference technology has been researched extensively in recent years. However, the development of clinically suitable, safe and effective drug delivery vehicles is still required.

Areas covered: This paper reviews the recent advances of non-viral delivery of small interfering RNA (siRNA) by nanoparticles, including biodegradable nanoparticles, liposomes, polyplex, lipoplex and dendrimers. The characteristics, composition, preparation, applications and advantages of different nanoparticle delivery strategies are also discussed in detail, along with the recent progress of non-viral nanoparticle carrier systems for siRNA delivery in preclinical and clinical studies.

Expert opinion: Non-viral carrier systems, especially nanoparticles, have been investigated extensively for siRNA delivery, and may be utilized in clinical applications in the future. So far, a few preliminary clinical trials of nanoparticles have produced promising results. However, further research is still required to pave the way to successful clinical applications. The most important issues that need to be focused on include encapsulation efficiency, formulation stability of siRNA, degradation in circulation, endosomal escape and delivery efficiency, targeting, toxicity and off-target effects. Pharmacology and pharmacokinetic studies also present another great challenge for nanoparticle delivery systems, owing to the unique nature of siRNA oligonucleotides compared with small molecules.     

Strategies for delivering local anesthetics to the skin: focus on liposomes,solid lipid nanoparticles,hydrogels and patches

Introduction: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions.

Areas covered: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches.

Expert opinion: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia.     

Polymeric colloidal particulate systems: intelligent tools for intracellular targeting of antileishmanial cargos

Introduction: Targeted cargo delivery systems can overcome drawbacks associated with antileishmanials delivery, by defeating challenges of physiological barriers. Various colloidal particulate systems have been developed in the past; few of them even achieved success in the market, but still are limited in some ways.

Areas covered: This review is focused on the pathobiology of leishmaniasis, interactions of particulate systems with biological environment, targeting strategies along with current conventional and vaccine therapies with special emphasis on polymeric nanotechnology for effective antileishmanial cargo delivery.

Expert opinion: The problems concerned with limited accessibility of chemotherapeutic cargos in conventional modes to Leishmania-harboring macrophages, their toxicity, and resistant parasitic strain development can be sorted out through target-specific delivery of cargos. Vaccination is another therapeutic approach employing antigen alone or adjuvant combinations delivered by means of a carrier, and can provide preventive measures against human leishmaniasis (HL). Therefore, there is an urgent need of designing site-specific antileishmanial cargo carriers for safe and effective management of HL. Among various colloidal carriers, polymeric particulate systems hold tremendous potential as an effective delivery tool by providing control over spatial and temporal distribution of cargos after systemic or localized administration along with enhancing their stability profile at a comparatively cost-effective price leading to improved chances of commercial applicability.     

Cellular uptake and transport of gold nanoparticles incorporated in a liposomal carrier

Recent interest in using gold nanoparticles (Au NPs) for therapy in radiation medicine has motivated development of a liposome-based system to enhance their delivery to cells. In this study, liposomes were demonstrated to perform like a “Trojan Horse” to deliver small (1.4 nm) Au NPs into tumor cells by overcoming the energetically unfavorable endocytosis process for small NPs. The results reveal that the liposomal approach provides a thousand-fold enhancement in the cellular uptake of the small Au NPs. Real-time intracellular tracking of the Au NP–liposomes revealed an average speed of 12.48 ± 3.12 μm/hr for their intracellular transport. Analysis of the time-dependent intracellular spatial distribution of the Au NP–liposomes demonstrated that they reside in lysosomes (final degrading organelles) within 40 minutes of incubation. Knowledge gained in these studies opens the door to pursuing liposomes as a viable strategy for delivery of Au NPs in radiation therapy applications.From the Clinical EditorGold nanoparticles (Au NPs) as part of an optimized liposome-based delivery system have been proposed for therapy in radiation medicine. The approach resulted in a thousand-fold enhancement in the cellular uptake of Au NPs compared to conventional delivery methods, with the nanoparticles residing in lysosomes within 40 minutes of incubation.     

‘Smart’ nanoparticles as drug delivery systems for applications in tumor therapy

Introduction: In the therapy of clinical diseases such as cancer, it is important to deliver drugs directly to tumor sites in order to maximize local drug concentration and reduce side effects. This objective may be realized by using ‘smart’ nanoparticles (NPs) as drug delivery systems, because they enable dramatic conformational changes in response to specific physical/chemical stimuli from the diseased cells for targeted and controlled drug release.

Areas covered: In this review, we first briefly summarize the characteristics of ‘smart’ NPs as drug delivery systems in medical therapy, and then discuss their targeting transport, transmembrane and endosomal escape behaviors. Lastly, we focus on the applications of ‘smart’ NPs as drug delivery systems for tumor therapy.

Expert opinion: Biodegradable ‘smart’ NPs have the potential to achieve maximum efficacy and drug availability at the desired sites, and reduce the harmful side effects for healthy tissues in tumor therapy. It is necessary to select appropriate NPs and modify their characteristics according to treatment strategies of tumor therapy.     

Targeted thermosensitive liposomes: an attractive novel approach for increased drug delivery to solid tumors

Introduction: Currently available chemotherapy is hampered by a lack in tumor specificity and resulting toxicity. Small and long-circulating liposomes can preferentially deliver chemotherapeutic drugs to tumors upon extravasation from tumor vasculature. Although clinically used liposomal formulations demonstrated significant reduction in toxicity, enhancement of therapeutic activity has not fully met expectations.

Areas covered: Low drug bioavailability from liposomal formulations and limited tumor accumulation remain major challenges to further improve therapeutic activity of liposomal chemotherapy. The aim of this review is to highlight strategies addressing these challenges. A first strategy uses hyperthermia and thermosensitive liposomes to improve tumor accumulation and trigger liposomal drug bioavailability. Image-guidance can aid online monitoring of heat and drug delivery and further personalize the treatment. A second strategy involves tumor-specific targeting to enhance drug delivery specificity and drug internalization. In addition, we review the potential of combinations of the two in one targeted thermosensitive-triggered drug delivery system.

Expert opinion: Heat-triggered drug delivery using thermosensitive liposomes as well as the use of tumor vasculature or tumor cell-targeted liposomes are both promising strategies to improve liposomal chemotherapy. Preclinical evidence has been encouraging and both strategies are currently undergoing clinical evaluation. A combination of both strategies rendering targeted thermosensitive liposomes (TTSL) may appear as a new and attractive approach promoting tumor drug delivery.     

Liposomal delivery of proteins and peptides

Introduction: A number of delivery issues exist for biotech molecules including peptides, proteins and gene-based medicines that now make up over 60% of the drug pipeline. The problems comprise pharmaceutical ad biopharmaceutical issues. One of the common approaches to overcome these issues is the use of a carrier and liposomes as carriers have been investigated extensively over the last decade.

Areas covered: The review has been discussed in terms of formulation and preclinical development studies and in vivo studies encompassing different delivery routes including parenteral, oral, buccal, pulmonary, intranasal, ocular and transdermal involving liposomes as carriers. Important research findings have been tabulated under each side heading and an expert opinion has been summarised for each delivery route.

Expert opinion: The conclusion and expert opinion – conclusion sections discuss in detail troubleshooting aspects related to the use of liposomes as carriers for delivery of biopharmaceutical moieties and scrutinises the aspects behind the absence of a protein/peptide-containing liposome in market.     

Current options for drug delivery to the spinal cord

Introduction: Spinal cord disorders (SCDs) are among the most devastating neurological diseases, due to their acute and long-term health consequences, the reduced quality of life and the high economic impact on society. Here, drug administration is severely limited by the blood–spinal cord barrier (BSCB) that impedes to reach the cord from the bloodstream. So, developing a suitable delivery route is mandatory to increase medical chances.

Areas covered: This review provides an overview of drug delivery systems used to overcome the inaccessibility of the cord. On one side, intrathecal administration, either with catheters or with biomaterials, represents the main route to administer drugs to the spinal cord; on the other side, more recent strategies involve chemical or electromagnetic disruption of the barrier and synthesis of novel functionalized compounds as nanoparticles and liposomes able to cross BSCB.

Expert opinion: Both the multifactorial pathological progression and the restricted access of therapeutic drugs to the spine are probably the main reasons behind the absence of efficient therapeutic approaches for SCDs. Hence, very recent highlights suggest the use of original strategies to overcome the BSCB, and new multidrug delivery systems capable of local controlled release of therapeutic agents have been developed. These issues can be addressed by using nanoparticles technology and smart hydrogel drug delivery systems, providing an increased therapeutic compound delivery in the spinal cord environment and multiple administrations able to synergize treatment efficacy.     

Recent advances in brain tumor-targeted nano-drug delivery systems

Introduction: Brain tumors represent one of the most challenging and difficult areas in unmet medical needs. Fortunately, the past decade has seen momentous developments in brain tumor research in terms of brain tumor-targeted novel nano-drug delivery systems with significant important superiority over conventional formulations with respect to decreased toxicity and improved pharmacokinetics/pharmacodynamics.

Area covered: This review first introduces the characteristics of the two major obstacles in brain-tumor targeted delivery, blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), and then reviews recent advances in brain tumor-targeted novel nano-drug delivery systems according to their targeting strategies aimed at different stages of brain tumor development and growth.

Expert opinion: Based on continuously changing vascular characteristics of brain tumors at different development and growth stages, we propose the concept of ‘whole-process targeting’ for brain tumor for nano-drug delivery systems, referring to a series of overall targeted drug delivery strategies aimed at key points during the whole development of brain tumors.     

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Introduction: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery.

Areas covered: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations.

Expert opinion: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.     

Oligonucleotide delivery in cancer therapy

Importance of the field: Cancer is frequently caused by altered protein expression. Oligonucleotides (ONs) are short synthetic nucleic acid fragments, able to selectively correct protein expression into cells by different mechanisms. However, biological barriers hamper the therapeutic use of ONs without suitable delivery strategies.

Areas covered in this review: This review summarizes the most meaningful non-viral strategies for ON delivery, including the chemical modifications of the ON backbone and non-viral delivery systems.

What the reader will gain: The reader will gain an update of the main strategies for ON delivery in cancer. Advantages and limits of each approach are underlined. Emphasis is given to the delivery strategies that contributed to bringing ONs into clinical trials.

Take home message: In the long story of ONs for cancer therapy, the development of delivery strategies has led, in the last few years, to different opportunities to use the high therapeutic potential of these molecules in humans.