Physical mechanisms and methods employed in drug delivery to tumors

In addition to several well-known drug delivery strategies developed to facilitate effective chemotherapy with anticancer agents, some new approaches have been recently established, based on specific effects arising from the applications of ultrasound, magnetic and electric fields on drug delivery systems. This paper gives an overview of newly developed methods of drug delivery to tumors and of the related anticancer therapies based on the combined use of different physical methods and specific drug carriers. The conventional strategies and new approaches have been put into perspective to revisit the existing and to propose new directions to overcome the threatening problem of cancer diseases.     

Challenges and Future Prospects for the Delivery of Biologics: Oral Mucosal,Pulmonary, and Transdermal Routes

Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers. While all these routes avoid transit through the gastrointestinal tract, each has its own strengths and weaknesses that may be optimal for specific classes of compounds. Buccal and sublingual delivery enable rapid drug uptake through a relatively permeable barrier but are limited by small epithelial surface area, stratified epithelia, and the practical complexities of maintaining a drug delivery system in the mouth. Pulmonary delivery accesses the highly permeable and large surface area of the alveolar epithelium but must overcome the complexities of safe and effective delivery to the alveoli deep in the lung. Transdermal delivery offers convenient access to the body for extended-release delivery via the skin surface but requires the use of novel devices and formulations to overcome the skin’s formidable stratum corneum barrier. New technologies and strategies advanced to overcome these challenges are reviewed, and critical views in future developments of each route are given.     

When analoging is not enough: scaffold discovery in medicinal chemistry

Importance of the field: As an integral part of lead generation and optimization, scaffold discovery has broad implications in drug discovery. Currently available chemical scaffolds might be inadequate to provide drug-like ligands for new targets such as phosphatases and protein-protein interactions and therapeutically useful chemical space needs to be continuously explored. New scaffolds are often desired to overcome major hurdles (e.g., potency plateau, selectivity, pharmacokinetics, etc.) in lead generation and optimization. Timely discovery of proof-of-concept compounds facilitates target validation, diversifies clinical candidates and improves the overall success rate of drug discovery. Areas covered in this review: This analysis discusses the strategies involved in finding new scaffolds (i.e., fragment-, ligand- and structure-based design) and their applications (e.g., improve potency/selectivity, multiple ligand design, protein-protein interactions, etc.) in drug discovery. What the reader will gain: The readers will learn the strategies involved in scaffold design and the problems that they solve. They will also gain the understanding of the circumstances suitable for using scaffold design. Take home message: Scaffold is defined by the authors as a biological target dependent concept. Therapeutically useful scaffolds are limited and the identification of new scaffolds is sometimes required to overcome major optimization hurdles. However, depending on the promiscuity of the binding pocket of the target and the validity of the optimization protocol, finding better scaffolds can be a challenging task. Several strategies in scaffold discovery have emerged or matured owing to recent trends such as pursuit of targets from new proteomic families, lack of validated targets, advances in synthesis and biological assays and adoption of in vitro activity-driven screening paradigms.     

Drug delivery to inflammation based on nanoparticles surface decorated with biomolecules

Anti-inflammatory molecules often display little affinity for inflamed tissues, leading to low accumulation into this site of action (and inefficiency), and high incidence of severe side effects. To face the problem, numerous strategies have been proposed, i.e., chemical modifications to the drug molecule, and engineering of drug nanocarriers. The later approach to the problem can result in optimized drug biodistribution and concentration into the target region, thus enhancing the anti-inflammatory effect while reducing the associated drug toxicity. Such nanoparticulate systems offer remarkable possibilities when they are made of biodegradable polymers, lipid-based structures, and/or inorganic particles. Recent advances in the field have been devoted to the optimization of the in vivo fate and effectiveness of these drug nanocarriers, e.g., passive targeting strategies based on the functionalization of nanoparticle surface with special biomolecules. In this contribution, we analyze the possibilities and future perspectives of nanoparticle therapy in inflammatory processes.     

Lipid nanoemulsions for anti-cancer drug therapy

Multifunctional lipid nanoemulsions have shown to combine several advantages e.g. tissue targeting, cell targeting, imaging analysis, barrier permeability enhancement, and therapeutic purposes. Depending on the choice of lipid composition, surfactants and additional surface modifiers ratio, different drug loadings may be achieved and exploited for drug delivery in cancer chemotherapy. However, a safe and effective delivery system for cancer therapy should also be able to overcome the major impediment of multidrug resistance. Several strategies have been tested in nanoemulsions including P-glycoprotein-mediated drug resistance. The present review focuses on a comprehensive discussion of the use of nanoemulsions in anti-cancer therapy, reporting the technological aspects of pharmaceutical formulation of these carriers, and exploiting their advantages in siRNA therapy.     

New technologies for immunotherapy against cancer: development of cell expansion technology and viruses as immune boosters

Dendritic cells (DCs) play a crucial role in maintaining the immune system. Although DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, clinical efficacies have been still unsatisfactory. To improve the clinical outcome of DC-based cancer immunotherapy, we are now focusing on 1) increase of numbers of therapeutic immune cells, i.e., DCs, and 2) the development of new methods for stimulating them. We have recently established a possible breakthrough, a simple cytokine-based culture method to realize a log-scale order of functional myeloid-type murine/human DCs. Moreover, we demonstrated that DCs activated by replication-deficient recombinant Sendai virus (rSeV) were highly effective than that seen in the use of current DC vaccine stimulated by conventional cytokines etc., for immunotherapy against malignancies. Therefore, our study strongly suggests that these improvements could overcome the current limitations of DC-based immunotherapy for malignancies.     

Microneedles as transdermal delivery systems: combination with other enhancing strategies

Transdermal drug delivery has exhaustively been studied over the past decades due to its multiple advantages over other administration routes; however, drugs that can be administered by this via are few owe to the stratum corneum permeability properties. Recently, several strategies to bypass the upper-layer skin barrier have been developed. One of the latest advances in this area has been the use of micro-scale needles, which painlessly pierce skin, increasing the passage of drugs with unfavourable skin permeability (i.e., low potent, hydrophilic, high molecular drugs) by several orders of magnitude, by bypassing the stratum corneum. Microneedles have shown to be safe and easy-to-use for drug administration, a nouvelle alternative to hypodermic needle injections, and an array in which drugs can be included to attain a controlled release as to achieve a higher drug delivery. Several works have demonstrated that such devices dramatically increase transdermal delivery of large molecules, thus nowadays microneedles have been regarded as a potential technology approach to be employed alone or with other enhancing methods such as electroporation and iontophoresis, as well as with different drug carriers (e.g., lipid vesicles, micro- and nanoparticles). Hence, this review is mainly focused on presenting the results obtained when combining microneedles with a variety of strategies to ease drug diffusion through skin, including physical enhancers and drug carrier systems.     

Use of monetary reinforcers by cocaine-dependent outpatients.

Monetary reinforcers have not been widely used as contingent reinforcers in the treatment of drug abuse, despite their demonstrated effectiveness. This is primarily due to concern that drug abusers will use monetary reinforcers to procure drugs. The present study addressed this concern by examining 48 cocaine-dependent outpatients' biweekly self-reports of how they used their earned reinforcers. For each subject, their reinforcement usage was classified into 12 higher-order categories and 34 subcategories. Usage proportions were calculated for each. Results indicated that monetary reinforcers were used very infrequently to acquire drugs or alcohol (2%). Reinforcers were used primarily for daily life activities (25%) (e.g., food and gas), money-related uses (18%) (e.g., savings and repaying debts), personal use (15%) (e.g., cosmetics and clothes), and household items (11%) (e.g., rent and bills). These findings challenge the concern that drug abusers use monetary reinforcers to purchase drugs and have important implications for the use of contingent monetary reinforcers in treatment settings.     

Delivery strategies for macromolecular drugs in cancer therapy

With the development of biotherapy, biomacromolecular drugs have gained tremendous attention recently, especially in drug development field due to the sophisticated functions in vivo. Over the past few years, a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability, e.g., the instability and easily restricted by physiologic barriers. The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life, increase the bioavailability, or improve patient compliance, which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs. In this review, recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized, mainly drawing on the development over the last five years.     

Outpatient antibiotic stewardship: Interventions and opportunities

Improving the use of antibiotics across the continuum of care is a national priority. Data outlining the misuse of antibiotics in the outpatient setting justify the expansion of antibiotic stewardship programs (ASPs) into this health care setting; however, best practices for outpatient antibiotic stewardship (AS) are not yet defined. In a companion article, we focused on recommendations to overcome challenges related to the implementation of an outpatient ASP (e.g., building the AS team and defining program metrics). In this document, we outline AS interventions that have demonstrated success and highlight opportunities to enhance AS in the outpatient arena. This article summarizes examples of point-of-care testing, policies and interventions, and education strategies to improve antibiotic use that can be used in the outpatient setting.     

Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging,drug targeting and delivery

The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as “overexpressed” biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug, which ultimately leads to effective and safe cancer therapy.     

Cell penetrating peptides for in vivo molecular imaging applications

Cell penetrating peptides (CPPs) are a relatively new class of peptides that have the promising capability to cross cell membranes. While details remain to be resolved, various non-receptor-mediated endocytic pathways likely contribute most to the cell penetrating properties of these peptides. CPPs have been used to deliver many different cargos - ranging from radionuclides and other peptides to antibodies and nanoparticles - into cells. Besides many different drug delivery applications, CPPs have also seen a limited use in molecular imaging. Molecular imaging of intracellular and intranuclear targets, by techniques such as SPECT, PET, optical imaging, and MRI, relies heavily on the delivery of contrast agents to the cytoplasm and/or nuclei of the target tissue. Therefore, the number of applications in molecular imaging of intracellular targets has remained relatively low, because of the effective barrier presented by the cell membrane. One of the key strategies to overcome this challenge is the introduction of membrane-transducing peptides in the design of new contrast agents. This review presents an overview of the literature on CPPs, focusing on their use for molecular imaging. Applications using proteins and peptides, DNA/RNA, and CPP-loaded cells as the imaging agents will be looked at. Moreover, the difficulties and pitfalls regarding the use of CPPs in molecular imaging will be discussed.     

Transporter targeted drug delivery

The pharmacological behavior of various drugs is severely affected by biological barriers such as epithelial tight junctions, efflux proteins and metabolizing enzymes. Apart from the biological barriers, physicochemical properties of drug molecules such as molecular weight, lipophilicity, surface charge and solubility also play an important role in absorption characteristics of drug candidates. Pharmacological properties affected by efflux pumps such as P-gp and MRPs include bioavailability, hepatobiliary and urinary excretion of drugs as well as drug metabolites. This leads to sub-therapeutic concentrations of various potential drugs at the target site. One of the strategies to overcome these biological barriers is transporter targeted prodrug design. Prodrug derivatization targeting membrane transporters and receptors improves drug absorption. Various prodrugs which have been synthesized so far demonstrated enhanced bioavailability and tissue specificity. This review mainly focuses on the efflux pumps which play an important role in drug absorption and a few strategies to overcome these efflux pumps.     

Drug delivery systems for brain tumor therapy

Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.     

Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride

Context: Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50–60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment.

Objective: The main aim of this review is to summarize metformin HCl-loaded micro- and nanoparticulate drug delivery systems.

Method: The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro- and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed.

Conclusion: Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.     

The tumor stroma as mediator of drug resistance--a potential target to improve cancer therapy?

Tumors irrespective of their origin are heterogeneous cellular entities whose growth and progression greatly depend on reciprocal interactions between genetically altered (neoplastic) cells and their non-neoplastic microenvironment. Thus, microenvironmental factors promote many steps in carcinogenesis, e.g. proliferation, invasion, angiogenesis, metastasis and chemoresistance. Drug resistance, either intrinsic or acquired, essentially limits the efficacy of chemotherapy in many cancer patients. To some extent, this resistance is maintained by reduced drug accumulation, alterations in drug targets and increased repair of drug-induced DNA damage. However, the pivotal mechanism by which tumor cells elude the cytotoxic effect of chemotherapeutic drugs is their efficient protection from induction and excecution of apoptosis. It is meanwhile well established that cellular and non-cellular components of the tumoral microenvironment, e.g. myofibroblasts and extracellular matrix (ECM) proteins, respectively, contribute to the anti-apoptotic protection of tumor cells. Cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins and other ECM receptors which are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified as suitable molecular targets to overcome chemoresistance. Accordingly, several therapeutic strategies based on these targets have been already elaborated and tested in preclinical and clinical studies, including inhibitors and blocking antibodies for CD44/hyaluronan, integrins, L1CAM and CXCL12. Even though these approaches turned out to be promising, the upcoming challenge will be to prove the efficacy of these strategies in improving treatment and prognosis of cancer patients.     

Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations.

Drug transport in the central nervous system is highly regulated not only by the blood-brain and the blood-cerebrospinal fluid barriers but also in brain parenchyma. The novel localization of drug transporters in brain parenchyma cells, such as microglia and astrocytes, suggest a reconsideration of the present conceptualization of brain barriers as it relates to drug transport. That is, the cellular membranes of parenchyma cells act as a second "barrier" to drug permeability and express transporters whose properties appear similar to those localized at the conventional brain barriers. This review will focus on the molecular characteristics, localization, and substrate specificities of several classes of well known membrane drug transporters (i.e., the organic cation, organic anion, nucleoside, P-glycoprotein, and multidrug resistance proteins) in the brain. Comparisons to similar transporters localized within the peripheral system and clinical implications of the functional expression of specific drug transport families will be discussed when appropriate. Nutrient and neurotransmitter transporters, whose characteristics have been reviewed extensively elsewhere, will not be considered in this review.