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.     

Recent trends in targeted anticancer prodrug and conjugate design

Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that result into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design have focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinge on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented.     

Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology

At present, brain tumor is among the most challenging diseases to treat and the therapy is limited by the lack of effective methods to deliver anticancer agents across the blood-brain barrier (BBB). BBB is a selective barrier that separates the circulating blood from the brain extracellular fluid. In its neuroprotective function, BBB prevents the entry of toxins, as well as most of anticancer agents and is the main impediment for brain targeted drug delivery approaches. Nanotechnology-based delivery systems provide an attractive strategy to cross the BBB and reach the central nervous system (CNS). The incorporation of anticancer agents in various nanovehicles facilitates their delivery across the BBB. Moreover, a more powerful tool in brain tumor therapy has relied surface modifications of nanovehicles with specific ligands that can promote their passage through the BBB and favor the accumulation of the drug in CNS tumors. This review describes the physiological and anatomical features of the brain tumor and the BBB, and summarizes the recent advanced approaches to deliver anticancer drugs into brain tumor using nanobiotechnology-based drug carrier systems. The role of specific ligands in the design of functionalized nanovehicles for targeted delivery to brain tumor is reviewed. The current trends and future approaches in the CNS delivery of therapeutic molecules to tumors are also discussed.     

Nanoparticles as delivery carriers for anticancer prodrugs

INTRODUCTION: Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies. AREAS COVERED: This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review. EXPERT OPINION: More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.     

Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors

In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.     

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.     

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.     

Anticancer prodrugs: an overview of major strategies and recent developments

Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of anticancer agents. The chemical implementation of prodrug approaches is illustrated through selected drug candidates.     

Nanoparticles as delivery carriers for anticancer prodrugs

Introduction: Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies.

Areas covered: This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review.

Expert opinion: More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.     

Amino acids as promoieties in prodrug design and development

Prodrugs are biologically inactive agents that upon biotransformation in vivo result in active drug molecules. Since prodrugs might alter the tissue distribution, efficacy and the toxicity of the parent drug, prodrug design should be considered at the early stages of preclinical development. In this regard, natural and synthetic amino acids offer wide structural diversity and physicochemical properties. This review covers the use of amino acid prodrugs to improve poor solubility, poor permeability, sustained release, intravenous delivery, drug targeting, and metabolic stability of the parent drug. In addition, practical considerations and challenges associated with the development of amino acid prodrugs are also covered.     

Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy

Combination therapy for the treatment of cancer is becoming more popular because it generates synergistic anticancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. In recent years, nanotechnology-based combination drug delivery to tumor tissues has emerged as an effective strategy by overcoming many biological, biophysical and biomedical barriers that the body stages against successful delivery of anticancer drugs. The sustained, controlled and targeted delivery of chemotherapeutic drugs in a combination approach enhanced therapeutic anticancer effects with reduced drug-associated side effects. In this article, we have reviewed the scope of various nanotechnology-based combination drug delivery approaches and also summarized the current perspective and challenges facing the successful treatment of cancer.     

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.     

Modulation of camptothecin analogs in the treatment of cancer: a review

The topoisomerase I inhibitors reviewed in this paper are all semisynthetic analogs of camptothecin (CPT). Modulation of this intranuclear enzyme translates clinically in to antitumor activity against a broad spectrum of tumors and is therefore the subject of numerous investigations. We present preclinical and clinical data on CPT analogs that are already being used in clinical practice [i.e. topotecan and irinotecan (CPT-11)] or are currently in clinical development (e.g. 9-aminocamptothecin, 9-nitrocamptotecin, lurtotecan, DX 8951f and BN 80915), as well as drugs that are still only developed in a preclinical setting (silatecans, polymer-bound derivates). A variety of different strategies is being used to modulate the systemic delivery of this class of agents, frequently in order to increase antitumor activity and/or reduce experienced side effects. Three principal approaches are discussed, including: (i) pharmaceutical modulation of formulation vehicles, structural alterations and the search for more water-soluble prodrugs, (ii) modulation of routes of administration and considerations on infusion duration, and (iii) both pharmacodynamic and pharmacokinetic biomodulation.     

Prodrug strategy for enhancing drug delivery via skin

Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.     

Development of cytarabine prodrugs and delivery systems for leukemia treatment

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin's lymphoma. The drug has a short plasma half-life, low stability and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in Phase III trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt, Pacira Pharmaceuticals Inc., New Jersey, USA) has been approved for the treatment of lymphomatous meningitis.

Areas covered in this review: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy.

What the reader will gain: This review provides in-depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provides insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability.

Take home message: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents.     

Prodrugs for targeted tumor therapies: recent developments in ADEPT, GDEPT and PMT

The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC(50) values of down to 110 fM.     

Loco-regional administration of nanomedicines for the treatment of lung cancer

Lung cancer poses one of the most significant challenges to modern medicine, killing thousands every year. Current therapy involves surgical resection supplemented with chemotherapy and radiotherapy due to high rates of relapse. Shortcomings of currently available chemotherapy protocols include unacceptably high levels of systemic toxicity and low accumulation of drug at the tumor site. Loco-regional delivery of nanocarriers loaded with anticancer agents has the potential to significantly increase efficacy, while minimizing systemic toxicity to anticancer agents. Local drug administration at the tumor site using nanoparticulate drug delivery systems can reduce systemic toxicities observed with intravenously administered anticancer drugs. In addition, this approach presents an opportunity for sustained delivery of anticancer drug over an extended period of time. Herein, the progress in the development of locally administered nanomedicines for the treatment of lung cancer is reviewed. Administration by inhalation, intratumoral injection and means of direct in situ application are discussed, the benefits and drawbacks of each modality are explored.     

Dendrimers as biopharmaceuticals: synthesis and properties

Two general aspects which need to be considered for the successful application of dendrimers for biomedical purposes are their availability at an acceptable cost and their suitability as regards their pharmacodynamic and pharmacokinetic properties. These two aspects are covered in this review. In the first part, synthetic strategies for the preparation of dendrimers are outlined and emphasis is given to recent work on methodologies whose aim is the development of more efficient routes to dendrimers in terms of the materials used for their synthesis as well as in terms of the procedures required for their purification. These include procedures involving double-stage and double exponential synthesis, orthogonal coupling strategies, self-assembly and solid-phase approaches, as well as particularly useful synthetic protocols such as those used in "click chemistry". The second part of the review deals with the way in which the size, chemical constitution and physicochemical properties of dendrimers used for drug delivery may affect pharmacodynamic and pharmacokinetic parameters which are important considerations for drug bioavailability. This is illustrated by an overview of examples from recent work involving non-steroidal anti-inflammatory drugs, anticancer drugs and antibacterials.     

Poly (ethylene glycol) prodrug for anthracyclines via N-Mannich base linker: Design, synthesis and biological evaluation

Poly (ethylene glycol)s (PEGs) are potential drug carriers for improving the therapeutic index of anticancer agents. In this work, a novel methodology for constructing PEG prodrug of anthracycline anticancer drugs was developed based on N-Mannich base of salicylamide and its 2-acyloxymethylated derivative. The resultant conjugates first subjected to in vitro hydrolysis testing, which revealed the release behavior of newly synthesized PEG prodrugs could be adjusted by the status of 2-hydroxy group of salicylamide. These PEG prodrugs also demonstrated superior cytotoxicity in antiproliferative assay. O-blocked doxorubicin prodrug with PEG20k as carrier was selected for further in vivo assessments and presented longer circulating life in pharmacokinetic experiment. This high molecular prodrug was also found to be more efficacious against S-180 xenografted tumor than equivalent amount of doxorubicin.