Prodrug Approaches for CNS Delivery

Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.     

Prodrugs--from serendipity to rational design

The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.     

Recent updates in utilizing prodrugs in drug delivery (2013–2015)

ABSTRACT

Introduction: Utilizing the prodrug approach as a method to overcome various pharmaceutical and pharmacokinetic barriers to drug delivery is significantly accelerating and achieving successes. In contrast to the older traditional prodrugs which suffer from decreased bioavailability and a high profile of side effects, due to activation at undesired sites, the targeted prodrug approach utilizes delivery systems to improve delivery for a wide range of therapeutics including anti-cancer, anti-bacterial and anti-inflammatory drugs.

Areas covered: Recent updates in utilization of prodrugs in drug delivery between 2013 and 2015 are discussed. Targeted prodrugs against cancer, solid tumors, microbial infections, inflammation and other diseases using advanced delivery systems such as theranostic approaches, siRNA, DOX immunoconjugate, C 60-ser carrier vector, biotinylated prodrug, human serum albumin (HSA) carrier and others are presented.

Expert opinion: Recent research efforts have been directed at developing targeted prodrugs to replace the classical prodrugs. The use of this approach has accelerated following the emergence of encouraging results from several studies on targeted prodrugs that have highlighted their higher efficiency and improved safety profiles.

Targeted prodrug delivery is now considered more than a chemical modification method. It is an applicable and promising approach and, in the future, better knowledge and wide application of this approach may be attained which may pave the way for more forward-thinking and creative techniques.     

Do prodrugs deliver?

This review examines the prodrug concept in the context of conventional prodrugs, which seek to increase systemic concentrations of a drug, and targeted prodrugs, which are designed to increase therapeutic ratio. In general, conventional prodrugs are designed to enhance oral absorption. With both types of prodrug, a pharmacokinetic/pharmacodynamic model must be created to understand the steps required and the barriers that need to be overcome to achieve success. This review highlights the role of polar surface area in identifying drugs that are suitable for oral absorption, and which have the required potency and retention at the intended site of pharmacology.     

Design of fatty acid conjugates for dermal delivery and topical therapeutics

The development of topical and transdermal drug delivery systems has aimed at overcoming the remarkably efficient barrier property of human skin by nontoxic and nonirritant methods. Numerous chemical and physical approaches have been investigated to overcome the skin's formidable barrier function. This article reviews two types of drug delivery approaches currently under investigation, which aim to increase drug permeability into and through the skin, by using fatty acid conjugates. The first approach uses fatty-acid conjugates as chemical enhancers for topical drugs while avoiding irritation, which is usually caused by the conventional use of free fatty acids. The second approach uses a conjugation of fatty acids to hydrophilic drug molecules to create effective topical prodrugs. The polyunsaturated fatty acid (PUFA) ester prodrugs for dermal delivery may be particularly promising and more advantageous by playing a role of mutual prodrugs. This article presents an overview of the ongoing research on fatty acid conjugates for dermal application. The concepts, potential uses, limitations as well as their safety considerations are described.     

New antiviral nucleoside prodrugs await application

In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.     

Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery

The use of the nasal route for drug delivery has attracted much interest in recent years in the pharmaceutical field. Local and principally systemic drug delivery can be achieved by this route of administration. But the nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration due to poor membrane permeability, rapid clearance and enzymatic degradation into the nasal cavity. Thus, alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems including liposomes, cyclodextrins, micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally. This review article discusses recent progress and specific development issues relating to colloidal drug delivery systems in nasal drug delivery.     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.     

新药研究中的前药原理

前药具有改变药物的理化性质 ,提高生物利用度 ,增加水溶性 ,减少不良反应 ,定位到达靶器官等特性。前药保持或增强原药的药效 ,同时又克服了原药的缺点。本文主要综合前药原理在新药设计中的典型实例 ,介绍前药原理的应用规律     

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.     

Transdermal delivery of nalbuphine and its prodrugs by electroporation.

The aim of this study was to assess the effects of electroporation on transdermal permeation of nalbuphine (NA) and its prodrugs. The permeation characteristics were investigated under various electrical factors and skin barriers to elucidate the mechanisms involved in transdermal delivery of NA and its prodrugs by skin electroporation. The in vitro permeation studies were performed using side-by-side diffusion cells. The various electrical factors investigated were pulse voltage, pulse duration and pulse number; the different skin barriers studied were intact hairless mouse skin, stratum corneum (SC)-stripped skin, delipid skin as well as furry Wistar rat skin. The prodrugs were fully converted to parent drug after skin permeation. Application of electroporation significantly enhanced transdermal permeation of NA and its prodrugs. The enhancement ratios were highest for NA and the four prodrugs showed the similar permeability after electroporation. The permeation amounts of NA and its prodrugs may be increased by application of higher pulse voltage, pulse duration as well as pulse number. Various kinetics and mechanisms were observed for the permeation of the hydrophilic NA and lipophilic nalbuphine enanthate through different skin barriers by applying electroporation. This study demonstrated that electroporation may enhance and control transdermal permeation of NA and its prodrugs. The results also indicated that the physicochemical properties of prodrug had significant effects on kinetics as well as mechanisms of transdermal permeation by electroporation.     

Perfluorocarbon compounds as vehicles for pulmonary drug delivery

Drug delivery to the diseased lung is hindered by the buildup of fluid and shunting of blood flow away from the site of injury. The use of perfluorocarbon compounds (PFCs) as drug delivery vehicles has been proposed to overcome these obstacles. This drug delivery approach is based on the unique properties of PFCs. For example, PFCs can homogeneously fill the lung and recruit airways by replacing edematous fluid. Analogously, drugs administered with a PFC vehicle are expected to be homogeneously distributed throughout the lung. At the same time, intrapulmonary administration of the drug will achieve higher drug concentrations in the lung than conventional approaches, while reducing systemic exposure. Unfortunately, PFCs are poor solvents for typical drug molecules. To overcome this obstacle, several approaches, such as dispersions, prodrugs, solubilizing agents and (micro)emulsions, are under investigation to develop homogeneous PFC-drug mixtures suitable for intrapulmonary administration.     

Nucleoside analogue delivery systems in cancer therapy

Nucleoside analogues (NAs) are important agents in the treatment of hematological malignancies. They are prodrugs that require activation by phosphorylation. Their rapid catabolism, cell resistance and overdistribution in the body jeopardize nucleoside analogue chemotherapy. Accordingly, therapeutic doses of NAs are particularly high and regularly have to be increased, resulting in severe toxicity and narrow therapeutic index. The major challenge is to concentrate the drug at the tumour site, avoiding its distribution to normal tissues. New drug carriers and biomaterials are being developed to overcome some of these obstacles. This review highlights novel NA delivery systems and discusses new technologies that could improve NA cancer therapy.     

Nucleoside analogue delivery systems in cancer therapy

Nucleoside analogues (NAs) are important agents in the treatment of hematological malignancies. They are prodrugs that require activation by phosphorylation. Their rapid catabolism, cell resistance and overdistribution in the body jeopardize nucleoside analogue chemotherapy. Accordingly, therapeutic doses of NAs are particularly high and regularly have to be increased, resulting in severe toxicity and narrow therapeutic index. The major challenge is to concentrate the drug at the tumour site, avoiding its distribution to normal tissues. New drug carriers and biomaterials are being developed to overcome some of these obstacles. This review highlights novel NA delivery systems and discusses new technologies that could improve NA cancer therapy.     

Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates.

A great deal of interest has surrounded the activities of monoclonal antibodies (mAbs), and mAb-drug, toxin and radionuclide conjugates for the treatment of human cancers. In the last few years, a number of new mAb-based reagents have been clinically approved (Rituxan, Herceptin, and Panorex), and several others are now in advanced clinical trials. Successful therapeutic treatment of solid tumors with drug conjugates of such macromolecules must overcome the barriers to penetration within tumor masses, antigen heterogeneity, conjugated drug potency, and efficient drug release from the mAbs inside tumor cells. An alternative strategy for drug delivery involves a two-step approach to cancer therapy in which mAbs are used to localize enzymes to tumor cell surface antigens. Once the conjugate binds to the cancer cells and clears from the systemic circulation, antitumor prodrugs are administered that are catalytically converted to active drugs by the targeted enzyme. The drugs thus released are capable of penetrating within the tumor mass and eliminating both cells that have and have not bound the mAb-enzyme conjugate. Significant therapeutic effects have been obtained using a broad range of enzymes along with prodrugs that are derived from both approved anticancer drugs and highly potent experimental agents. This review focuses on the activities of several mAb-enzyme/prodrug combinations, with an emphasis on those that have provided mechanistic insight, clinical activity, novel protein constructs, and the potential for reduced immunogenicity.     

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.     

Perfluorocarbon compounds as vehicles for pulmonary drug delivery

Drug delivery to the diseased lung is hindered by the buildup of fluid and shunting of blood flow away from the site of injury. The use of perfluorocarbon compounds (PFCs) as drug delivery vehicles has been proposed to overcome these obstacles. This drug delivery approach is based on the unique properties of PFCs. For example, PFCs can homogeneously fill the lung and recruit airways by replacing edematous fluid. Analogously, drugs administered with a PFC vehicle are expected to be homogeneously distributed throughout the lung. At the same time, intrapulmonary administration of the drug will achieve higher drug concentrations in the lung than conventional approaches, while reducing systemic exposure. Unfortunately, PFCs are poor solvents for typical drug molecules. To overcome this obstacle, several approaches, such as dispersions, prodrugs, solubilizing agents and (micro)emulsions, are under investigation to develop homogeneous PFC–drug mixtures suitable for intrapulmonary administration.     

Evaluation and prediction of drug permeation

A major challenge confronting the pharmaceutical scientist is to optimize the selective and efficient delivery of new active entities and drug candidates. Successful drug development requires not only optimization of specific and potent pharmacodynamic activity, but also efficient delivery to the target site. Following advances in rational drug design, combinatorial chemistry and high-throughput screening techniques, the number of newly discovered and promising active compounds has increased dramatically in recent years, often making delivery problems the rate-limiting step in drug research. To overcome these problems, a good knowledge of the pharmacokinetic barriers encountered by bioactive compounds is required. This review gives an overview of the properties of relevant physiological barriers and presents some important biological models for evaluation of drug permeation and transport. Physicochemical determinants in drug permeation and the relevance of quantitative and qualitative approaches to the prediction and evaluation of passive drug absorption are also discussed.     

Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.Key words: Barriers targeting, Tumor microenvironment, Tumor cells, Systematic targeted drug delivery     

Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin

Naltrexone (NTX) is an opioid antagonist used for treatment of narcotic dependence and alcoholism. Transdermal naltrexone delivery is desirable to help improve patient compliance. The purpose of this study was to increase the delivery rate of NTX across human skin by using lipophilic alkyl ester prodrugs. Straight-chain naltrexone-3-alkyl ester prodrugs of 2-7 carbons in chain length were synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The melting points, solubilities, and skin disposition of the drugs were determined. The prodrugs were almost completely hydrolyzed on passing through the skin and appeared as NTX in the receiver compartment. The mean NTX flux from the prodrug-saturated solutions exceeded the flux of NTX base by approximately 2-7-fold. The amount of drug detected in the skin was significantly greater after treatment with the prodrug solutions compared with treatment with NTX base. The extent of parent drug (NTX) regeneration in the intact skin ranged from 28 to 91%. Higher NTX regeneration percentages in skin appeared to correlate with increased drug delivery rates. Definitively, the highly oil-soluble prodrugs provide a higher NTX flux across human skin in vitro and undergo significant metabolic conversion in the skin.