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.     

Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target

A major hurdle impeding the successful clinical development of drug candidates can be poor intestinal permeability. Low intestinal permeability may be enhanced by a prodrug approach targeting membrane transporters in the small intestine. Transporter specificity, affinity, and capacity are three factors in targeted prodrug design. The human apical sodium dependent bile acid transporter (SLC10A2) belongs to the solute carrier family (SLC) of transporters and is an important carrier protein expressed in the small intestine. In spite of its appearing to be an excellent target for prodrug design, few studies have targeted human apical sodium dependent bile acid transporter (hASBT) to improve oral bioavailability. This review discusses bile acids including their chemistry and their absorptive disposition. Additionally, hASBT-mediated prodrug targeting is discussed, including QSAR, in vitro models for hASBT assay, and the current progress in utilizing hASBT as a drug delivery target.     

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.     

Targeted prodrug design to optimize drug delivery

Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.     

Impact of drug transporter studies on drug discovery and development

Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.     

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer’s disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates – such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.     

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.     

Brain drug targeting and gene technologies.

Brain drug targeting technology is based on the application of four gene technologies that enable the delivery of drugs or genes across the blood-brain barrier (BBB) in vivo. I) Genetic engineering is used to produce humanized monoclonal antibodies that target endogenous BBB transporters and act as vectors for delivery of drugs or genes to the human brain. The conjugate of a neurotherapeutic and a BBB transport vector is called a chimeric peptide. Epidermal growth factor chimeric peptides have been used for neuroimaging of brain cancer. Brain-derived neutrophic factor chimeric peptides have marked neuroprotective effects in brain stroke models. II) Imaging gene expression in the brain in vivo is possible with sequence-specific antisense radiopharmaceuticals, which are conjugated to BBB drug targeting vectors. III) Brain gene targeting technology enables widespread expression of an exogenous gene throughout the central nervous system following an intravenous injection of a non-viral therapeutic gene. IV) A BBB genomics program enables the future discovery of novel transport systems expressed at the BBB. These transporters may be carrier-mediated transport systems, active efflux transporters, or receptor-mediated transcytosis systems. The future discovery of novel BBB transport systems and the application of brain drug targeting technology will enable the delivery to the brain of virtually any neurotherapeutic, including small molecules, large molecules and gene medicines.     

Oral delivery of HIV-protease inhibitors

Strategies for optimizing the oral delivery of HIV-protease inhibitors draw from drug discovery efforts in molecular design, drug development tools in dosage formulation, and dosage regimen considerations in clinical medicine. This review outlines the evolution of these strategies for drugs that have been approved for human use, drug candidates still in development, and molecules that are no longer in development but from which valuable delivery information was obtained. Molecular design for obtaining desirable pharmacokinetics following oral administration primarily involved maximizing aqueous solubility and minimizing first-pass metabolism. Optimization of molecular design for oral drug delivery purposes is tempered by additional considerations for drug potency, toxicity, potential for interactions, and development of viral resistance. Strategies for improving oral bioavailability through dosage formulation use information from the effects of coadministered meals on drug plasma levels. Patient adherence to dosage regimens remains a major issue in assuring effective oral drug treatment and in preventing the development of resistance. Progress has been made in clinical studies where improved oral bioavailability and reductions in drug plasma level variability have been achieved with appropriate dosage regimen adjustment.     

Stability of peptides and therapeutic success in cancer

INTRODUCTION: Although naturally occurring peptides have been widely used as drugs, their rapid in vivo degradation by proteolysis and their interactions at multiple receptors are part of the reason for the limitation of their clinical applications. AREAS COVERED: This paper reviews peptide-metabolizing enzymes in the brain and intestinal brush-border membranes, and discusses potential strategies to improve biological activity, specificity and stability of peptides. The reader will gain, via some examples, an appreciation of the challenges involved in identifying peptides stability to improve their biological properties such as selectivity. EXPERT OPINION: Due to the metabolic process, it is crucial to follow the biodistribution of a peptide drug and/or a peptidic moiety in order to improve its biological properties such as selectivity. To these purposes, pseudopeptides and peptidomimetics preserving the biological properties of native peptides have been developed to increase their resistance to degradation and elimination, bioavailability and selectivity to become good drug candidates.     

Pharmacosomes: the lipid-based new drug delivery system

Lipid-based drug delivery systems have been investigated in various studies and shown their potential in controlled and targeted drug delivery. Pharmacosomes are amphiphilic phospholipid complexes of drugs bearing active hydrogen that bind to phospholipids. Pharmacosomes impart better biopharmaceutical properties to the drug, resulting in improved bioavailability. Pharmacosomes have been prepared for various non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic drugs. Developing the pharmacosomes of the drugs has been found to improve the absorption and minimize the gastrointestinal toxicity. This article reviews the potential of pharmacosomes as a controlled and targeted drug delivery system and highlights the methods of preparation and characterization.     

壳聚糖衍生物及其胶束：特性、功能化修饰和在药物传递系统中的应用

壳聚糖是一种天然多糖,具有无毒、可生物降解、生物相容性等诸多优点,但水溶性差的自身特点限制了其在药剂学中的应用,而其经合理的结构设计、修饰和优化,可获得性能良好的两亲性壳聚糖衍生物,这些衍生物在水溶液中能自组装成具有良好药物传输性能（如载药量、稳定性、刺激敏感性、靶向性等）的胶束,并被广泛应用于构建药物传递系统,以改善药物的溶解性、靶向性、生物利用度及耐药性．降低药物的毒副作用。综述壳聚糖衍生物结构对其胶束药物传输性能的影响以及壳聚糖衍生物及其胶束的功能化修饰和在药物传递系统中的应用。     

Role of polymer–drug conjugates in organ-specific delivery systems

Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer–drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting.     

Antiangiogenic anticancer strategy based on nanoparticulate systems

INTRODUCTION: Angiogenesis is a process that provides a blood supply for cancer cells. The discovery that the blockade of this blood supply results in the inhibition of cancer cell growth has been applied in cancer treatment. This antiangiogenic strategy is mainly directed at the inhibition of the binding process between proangiogenic growth factors and their receptors or the inhibition of the activity of proteolytic enzymes of the extracellular matrix. The toxicity of some antiangiogenic agents, such as small-molecule inhibitors, and the instability of antiangiogenic proteins require their formulation in an appropriate delivery system. On the other hand, active drug targeting to selective markers expressed on tumor vasculature could improve antiangiogenic treatment. AREAS COVERED: The present review focuses on nanoparticulate systems (nanoparticles, liposomes, polymeric micelles, etc.) because their properties could enable both the targeting of endothelial cells and the efficient delivery of antiangiogenic agents. The most important properties of nanoparticles that influence both processes, such as their size, charge and surface modification, are also discussed. Various examples illustrating the targeting ability of nanoparticles are reported, in particular conjugated nanoparticles targeting VEGF and its receptors, fibroblast growth factor and its receptors, EGFRs, MMPs, tubulin function and so on. EXPERT OPINION: Targeting of nanoparticles (e.g., by tumor-penetrating peptides) allows the co-administration of antiangiogenic and anticancer drugs, facilitates drug penetration into extravascular tumor tissue and improves the therapeutic effect at reduced drug doses.     

Current prodrug strategies for improving oral absorption of nucleoside analogues

Nucleoside analogues are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome), cytomegalovirus infections, cancer, etc. However, many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability. In order to get around this drawback, prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug. Alternatively, prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1. The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport, but is readily degraded to the parent drug once at the target. This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.     

Multifunctional porous silicon for therapeutic drug delivery and imaging

Major challenges in drug formulation are the poor solid state stability of drug molecules, poor dissolution/solubility and/or poor pharmacokinetic properties (bioavailability), which may lead to unreliable in vitro-in vivo (IVIV) correlation. To improve current therapeutical strategies, novel means to deliver poorly water soluble active pharmaceutical ingredients, as well as to target them to specific sites or cells in the body are needed. Biomedical applications of porous silicon (PSi) have been actively investigated during the last 10 years, especially in the areas of drug delivery and imaging, due to the biocompatibility and biodegradability of PSi materials, which makes them a potential candidate for controlled drug release. In addition, the unique pore sizes and easily functionalized surface properties of PSi materials allow high drug payloads and controlled kinetics from the drug release formulations. Modification of the PSi surface properties also facilitates biofunctionalization of the surface and the possibility to attach targeting moieties (e.g., antibodies and peptides), thus enabling effective targeting of the payload. In this review, we briefly address the production methodologies of PSi, and we will mainly present and discuss several examples about the biocompatibility of PSi, the most recent in vitro and in vivo applications of PSi as a carrier in drug/protein/peptide delivery and tissue engineering, as well as PSi as a platform for drug targeting and imaging.     

Amino acid transporters: Emerging roles in drug delivery for tumor-targeting therapy

Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid transporters as a component of tumortargeting therapy.In this review,we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy.Firstly,the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed.Secondly,the recognition requirements are discussed,focusing on the“acidbase”properties,conformational isomerism and structural analogues.Finally,recent developments in amino acid transporter-targeting drug delivery strategies are highlighted,including prodrugs and nanocarriers,with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis.We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.     

Kinetic and thermodynamic approaches to the drug targeting phenomena

The effectiveness of many promising drug candidates (e.g. anticancer agents) awaits the development of drug forms capable of delivery of their drug load specifically to particular sites of an organism or a cell. To make universal and efficient drug carriers, administered drug-loaded vehicles should be able to reach the pathologic zone, recognize and bind their targets at a therapeutic concentration before clearance from the organism. Numerous methods have been developed to couple drug vehicles with active targeting substances - including monoclonal antibodies and substrates or ligands for pathologic cell receptors. Other approaches have included the use of such factors as decreased pH and elevated activity of enzymes in tumor tissues and the hypoxic environment inside the tumor core. This review makes an attempt to analyze the main factors that influence targeting on the kinetic or thermodynamic level that may provide the basis for a strategy to develop and improve drug delivery systems.     

Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting

Nucleoside analogues are widely used for the treatment of antiviral infections and anticancer chemotherapy. However, many nucleoside analogues suffer from poor oral bioavailability due to their high polarity and low intestinal permeability. In order to improve oral absorption of these polar drugs, prodrugs have been employed to increase lipophilicity by chemical modification of the parent. Alternatively, prodrugs targeting transporters present in the intestine have been exploited to facilitate the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two successful valine ester prodrugs transported by the PepT1 transporter. Recently, research efforts have focused on design of prodrugs for tissue specific delivery to improve efficacy and safety. This review presents advances of prodrug approaches for improved oral absorption of nucleoside analogues and recent developments in tissue targeting.