Anti-Cancer Agents in Medicinal Chemistry

(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')

ISSN: 1871-5206

Anti-Cancer Agents in Medicinal Chemistry
Volume 6, Number 6, November 2006

Contents

Nanomedicine for Cancer
Guest Editor: Vladimir P. Torchilin


Editorial Pp. 501
V.P. Torchilin


Tumor Physiology and Delivery of Nanopharmaceuticals Pp. 503-512
R.B. Campbell
[Abstract]


Pharmacokinetics and Pharmacodynamics of Lipidic Nano Particles in Cancer Pp. 513-523
T.M. Allen, W. Cheng, J. Hare and K. Laginha
[Abstract]


Stimuli-Sensitive Polymeric Micelles as Anticancer Drug Carriers Pp. 525-535
K. Na, V.T. Sethuraman and Y.H. Bae
[Abstract]


New Generation of Liposomal Drugs for Cancer Pp. 537-552
T. Minko, R.I. Pakunlu, Y. Wang, J.J. Khandare and M. Saad
[Abstract]


Recent Developments in Polymeric Nanoparticle Engineering and Their Applications in Experimental and Clinical Oncology Pp. 553-561
S.M. Moghimi
[Abstract]


Nucleic Acid Based Therapeutics for Tumor Therapy Pp. 563-570
M. Ogris
[Abstract]


General Articles


3-(4'-Geranyloxy-3'-Methoxyphenyl)-2-trans Propenoic Acid: A Novel Promising Cancer Chemopreventive Agent Pp. 571-577
M. Curini, F. Epifano, S. Genovese, M.C. Marcotullio and L. Menghini
[Abstract]


The Role of Anticoagulation in Cancer Patients: Facts and Figures Pp. 579-587
F. De Lorenzo, O. Dotsenko, M.F. Scully and M. Tymoshchuk
[Abstract]


Mitotic Catastrophe as a Consequence of Chemotherapy Pp. 589-602
S. Mansilla, M. Bataller and J. Portugal
[Abstract]




Abstracts


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Editorial
V.P. Torchilin

Application of nanomedical approaches in experimental and clinical oncology for cancer diagnosis and therapy is growing exponentially. The main efforts are currently directed towards the development of nanocarrier-based tumor-specific delivery systems for therapeutic and diagnostic agents. Several review papers and books published within last few months provide good illustration to how broad these efforts are [1-8]. Still, there is a common goal in all studies on cancer nanomedicine – to prepare therapeutic and diagnostic nanopreparations, which are capable of minimizing undesirable side effects of therapeutic and diagnostic agents onto normal tissues and organs and maximizing their accumulation in tumors.

Certainly, in a single journal issue it is impossible to represent the existing variety of nanomedical approaches for cancer. The editor and the authors of this issue have been trying to pursue a more realistic goal – to provide potential readers with some biological and pharmacological backgrounds of cancer nanomedicine and illustrate the general approach with some representative examples showing how cancer nanotherapeutics are developed and investigated.

The opening paper of this issue by Dr. Campbell addresses some key aspects of tumor physiology, which have to be taken into account when developing cancer nanotherapeutics. Specific attention is paid here to tumor vasculature and its role in tumor accumulation of drug-loaded nanocarriers. The paper by Dr. Allen and coauthors discusses the most important features of pharmacokinetics and pharmacodynamics of nanoparticles in cancer using lipidic nanocarriers as an example. Next three papers are dealing with certain specific types on pharmaceutical nanocarriers and their application for cancer therapy. Dr. Bae and coauthors describe properties and application of polymeric micelles, which are successfully used to increase the solubility and bioavailability of poorly soluble anticancer drugs, and specifically concentrate on such micelles that can changed their properties in a desirable way when exposed to acidified surroundings in tumors or even inside tumor cells. Dr. Minko and coauthors concentrate on current situation with the development of the liposomal drugs for cancer and discuss new, more sophisticated liposomal preparations loaded with multicomponent drug systems, which can simultaneously overcome drug efflux pumps and enhance apoptosis in cancer cells. Dr. Moghimi is considering polymeric nanoparticles and current status on their engineering and application both in experimental and clinical oncology. These three papers on individual types of pharmaceutical nanocarriers for cancer allow for more clear understanding of general problems associated with the application of nanosized drug delivery systems and show also the specifics in the development and application of each particular system. The last paper of the issue by Dr. Ogris brings to light achievements and challenges associated with the use of nanoparticlate delivery systems for nucleic acid therapy of cancer, promising and fast growing area of research.

I believe that this issue will successfully introduce the readers to exciting and challenging area of cancer nanomedicine.

References

[1] Zamboni W.C. Clin Cancer Res, 2005, 11, 8230.

[2] Huynh G.H.; Deen D.F.; Szoka F.G., Jr. J Control Release, 2006, 110, 236.

[3] Cegnar M.; Kristl J.; Kos J. Expert Opin Biol Ther, 2005, 5, 1557.

[4] Vicent M.J.; Duncan R. Trends Biotechnol, 2006, 24, 39.

[5] Sapra P.; Tyagi P.; Allen T.M. Curr Drug Deliv, 2005, 2, 369.

[6] van Vlerken L.E.; Amiji M.M. Expert Opin Drug Deliv, 2006, 3, 205.

[7] Wu G.; Barth R.F.; Yang W.; Lee R.J.; Tjarks W.; Backer M.V.; Backer J.M. Anticancer Agents Med Chem, 2006, 6, 167.

[8] Torchilin V.P.; Ed. Delivery of Protein and Peptide Drugs in Cancer, 2006, Imperial College Press, London, UK.


Vladimir P. Torchilin
Department of Pharmaceutical Sciences
Northeastern University
Boston, MA 02115
USA


[Back to top]
Tumor Physiology and Delivery of Nanopharmaceuticals
R.B. Campbell

Over the past few decades significant advances have been made in the development of nanopharmaceuticals (including phospholipid and polymer-based therapeutics) against cancer. There is still, however, room for improvement. Today, many researchers are focusing on the development of innovative approaches to selectively deliver drugs to solid tumors, while minimizing insult to healthy tissues. Unfortunately, the majority of these efforts are confronted by physiological barriers that reduce the clinical dose required to effectively manage the disease state. In an effort to develop promising nanopharmaceutical products of the future, we review the most important problems facing drug delivery experts today. We discuss here, the physiological role of solid tumors in delivery and transport of nanopharmaceutical products. The nature of tumors in terms of their unique anatomical structure and functions is also discussed. Finally, an overview of ways to overcome physiological barrier functions and exploit tumor pathogenesis for therapeutic gain is provided.


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Pharmacokinetics and Pharmacodynamics of Lipidic Nano Particles in Cancer
T.M. Allen, W. Cheng, J. Hare and K. Laginha

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL^®, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL^® passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Lipo-somes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.


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Stimuli-Sensitive Polymeric Micelles as Anticancer Drug Carriers
K. Na, V.T. Sethuraman and Y.H. Bae

Amphiphilic block copolymers often form core-shell type micelles by self-organization of the blocks in an aqueous medium or under specific experimental conditions. Polymeric micelles constructed from these polymers that contain a segment whose physical or chemical properties respond to small changes in environmental conditions are collectively called ‘stimuli-sensitive’ micelles. This class of nano-scaled constructs has been investigated as a promising anti-cancer drug carrier because the micelles are able to utilize small environmental changes and modify drug release kinetics, biodistribution and the interactions with tissues and cells. This review summarizes the recent progress in stimuli-sensitive micelles for tumor chemotherapy, particularly for those responding to hyperthermic conditions, tumor pH and endosomal/lysosomal pH.


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New Generation of Liposomal Drugs for Cancer
T. Minko, R.I. Pakunlu, Y. Wang, J.J. Khandare and M. Saad

This review is focused on liposomes as a delivery system for anticancer agents and more specifically on the advantages of using liposomes as drug nanocarrier in cancer chemotherapy. The main advantages of liposomal drugs over the non-encapsulated drugs include: (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability to include several active ingredients in one complex liposomal drug delivery system (DDS). The review also includes our recent data on advanced liposomal anticancer drug delivery systems. As a conclusion we propose a novel liposomal DDS which includes inhibitors of pump resistance combined in one liposomal drug delivery system with an inhibitor of antiapoptotic cellular defense, an apoptosis inducer (a traditional anticancer drug) and a targeting moiety. The proposed drug delivery system utilizes a novel three tier approach, simultaneously targeting three molecular targets: (1) extracellular receptors or antigen expressed on the surface of plasma membrane of cancer cells in order to direct the whole system specifically to the tumor, preventing adverse side effects on healthy tissues; (2) drug efflux pumps in order to inhibit them and enhance drug retention by cancer cells, increasing intracellular drug accumulation and thereby limiting the need for prescribed high drug doses that cause adverse drug side effects; and (3) intracellular controlling mechanisms of apoptosis in order to suppress cellular antiapoptotic defense.


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Recent Developments in Polymeric Nanoparticle Engineering and Their Applications in Experimental and Clinical Oncology
S.M. Moghimi

Promising results have come from attempts to direct drugs, nucleic acids and diagnostic agents to tumours by using polymeric nanoparticles. Such carriers are versatile; their encapsulation capacity, drug release profile, and biological performance vary with their chemical makeup, morphology, and size. Polymeric nanoparticles may therefore be engineered for therapeutic and diagnostic purposes in accordance with the type, developmental stage and location of the cancer as well as the required route of administration. This article examines recent developments in design and engineering of polymeric nanoparticles and related platforms to include supramolecular systems such as nanocapsules and nanoparticle-based hydrogels, and assesses their potential diagnostic and therapeutic applications in experimental and clinical oncology.


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Nucleic Acid Based Therapeutics for Tumor Therapy
M. Ogris

Although being a heterogeneous disease, cancer has certain characteristic features which can be utilized for treatment with novel macromolecular therapeutics. The active cycling status of tumor cells, proliferating tumor endothelium and a leaky vasculature allow the targeted delivery of therapeutically active nucleic acids into tumor tissue. We and others have developed polycationic gene carriers forming so called polyplexes with nucleic acids. Cellular aspects like binding, internalization and intracellular fate were enlightened. Additionally, virus like domains were incorporated into the polyplex. Hydrophilic shielding domains protect the polyplex from unspecific interaction with blood components, targeting ligands allow cell specific binding and internalization into target cells, and membrane active peptides have a favorable influence on intracellular trafficking. Physical targeting of polyplexes, like locoregional hyperthermia and photo-chemical internalization (PCI) have been further used to enhance the efficiency of nucleic acid transfer. Therapeutic concepts were carried out in different tumor models in mice. Local application of synthetic, double stranded RNA led to eradication of intracranial glioblastoma. A gene directed enzyme prodrug approach utilizing site directed activation of cyclophosphamide with cytochrome P450 gave first, promising results.


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3-(4'-Geranyloxy-3'-Methoxyphenyl)-2-trans Propenoic Acid: A Novel Promising Cancer Chemopreventive Agent
M. Curini, F. Epifano, S. Genovese, M.C. Marcotullio and L. Menghini

3-(4'-Geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid is a secondary metabolite biosynthetically related to ferulic acid in which a geranyl chain is attached to the phenolic group, extracted from Acronychia baueri Schott (Fam. Rutaceae). In the last five years some of the pharmacological properties of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid and its semisynthetic derivatives began to be characterized. In particular the ethyl ester showed a series of interesting biological effects such colon and tongue cancers chemoprevention by dietary feeding in rats and other effects closely related to cancer growth and development. Then 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid becomes a novel candidate as chemopreventive drug for the cure of various types of cancer and synthesis of some novel derivatives of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid, other than esters, has been recently reported. The aim of this review is to examine in detail the properties of the title compound so far reported in the literature from a chemical and pharmacological point of view.


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The Role of Anticoagulation in Cancer Patients: Facts and Figures
F. De Lorenzo, O. Dotsenko, M.F. Scully and M. Tymoshchuk

Thromboembolic events contribute significantly to the morbidity and mortality in cancer. Effective and safe anticoagulation – mainstay in prevention and treatment of thrombosis – remains very challenging clinical task in oncology patients – population of high rate of treatment failure, bleeding complications and thromboembolic events recurrences. Prospective randomized clinical studies have documented that with advent of low molecular weight heparins new possibilities for thrombosis treatment and long-term prevention with more convenient and safe anticoagulation have emerged. Considerable advances have been achieved at present time in our understanding of the pathobiology of thrombogenesis in human malignancies, particularly of the interactions between coagulation cascade reactions and processes of tumor growth and dissemination. This builds up a new challenge for modern oncology – appreciation of the hypothesis of anti-malignant effects of anticoagulants, which could influence the outcome of human cancer. Antineoplastic effects of anti-thrombotic drugs have been reported in various experimental models. Heparins have been the most extensively studied and have been shown to reduce the primary tumour growth and its metastatic spread. Joint evidence from fundamental research and from several randomized clinical trials, observing beneficial impact of low molecular weight heparins therapy on cancer patients survival, dictate the need for further scientific steps to confirm biological effects of heparins in human malignancies. The evidence is started to accumulate, that clinically approved heparins have different abilities to influence some processes of metastasis spread. The experimental work towards development of heparin derivates with low anticoagulant activity, but with potential inhibitory effects on tumor cells migration is in progress.


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Mitotic Catastrophe as a Consequence of Chemotherapy
S. Mansilla, M. Bataller and J. Portugal

According to a widespread model, anti-cancer chemotherapy involves the triggering of tumor cells to undergo apoptosis, so apoptosis-resistant cells would be recalcitrant to such therapy. However, in addition to apoptosis, which is mainly dependent on the activity of the tumor suppressor protein p53, cells can be eliminated following DNA damage by other mechanisms. Mitotic catastrophe, a form of cell death that results from abnormal mitosis, is one such mechanism. While the term mitotic catastrophe has been used to describe a type of cell death that occurs during mitosis, there is still no broadly accepted definition. Occasionally, mitotic catastrophe is used restrictively for abnormal mitosis leading to cell death, which can occur through necrosis or apoptosis, rather than cell death itself. Although different classes of cytotoxic agents induce mitotic catastrophe, the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. Moreover, mitotic catastrophe can also develop because of aberrant re-entry of tumor cells into the cell cycle after prolonged growth arrest. Elucidation of the factors that regulate different aspects of treatment-induced mitotic catastrophe should assist in improving the efficacy of anti-cancer therapy, providing opportunities for the development of new drugs.