Showing papers by "Ruth Duncan published in 2006"

Polymer conjugates as anticancer nanomedicines

Abstract: Polymers can be conjugated to anticancer drugs and proteins to improve their therapeutic index. Some such conjugates are in routine clinical use and there are exciting advances in development, such as polymer-based combination therapies.

Polymer therapeutics--polymers as drugs, drug and protein conjugates and gene delivery systems: past, present and future opportunities.

Abstract: As the 21st century begins we are witnessing a paradigm shift in medical practice. Whereas the use of polymers in biomedical materials applications, for example as prostheses, medical devices, cont...

Polymer therapeutics for cancer : Current status and future challenges

Abstract: Drug delivery systems for cancer therapeutics have revolutionized medicine. Delivery systems have improved the efficacy and reduced the toxicity of current therapies and resulted in the development of new ones. Today, millions of cancer patients have directly benefited from drug delivery systems, and polymers have been at the frontline of these technological advances. Targeted delivery systems of chemotherapeutics to the tumour compartment can be achieved systemically, either passively or actively. Polymer conjugation radically changes the pharmacokinetics of the bound drug, and conjugates with prolonged circulation times target tumours passively via the enhanced permeability and retention (EPR) effect. Polymer conjugates can also be modified with moieties to directly target the tumour cells or the tumour vasculature. In this chapter, we review the successful clinical application of polymer-protein conjugates, and promising clinical results arising from trials with polymer-anticancer-drug conjugates. Over the last decade more than twelve polymer-drug conjugates have entered Phase I/II clinical trial as intravenously injectable anticancer agents. Only one of the polymer conjugates that has reached clinical trial directly targets tumour cells, while another one targets the tumour vasculature. Conjugation to polymers may save the fate of the many promising drug/peptide chemotherapies that fail each year due to high toxicity or poor pharmacokinetics. Yet, these technologies have not been exploited to their full potential. Only a few combinations of a limited number of chemotherapeutic drugs and polymer delivery systems are being tested in clinical and preclinical trials today. Furthermore, genomics and proteomics research is producing novel peptides, proteins and oligonucleotides that lack effective delivery systems. Thus, the full potential for drug delivery systems based on NCEs (new chemical entities), such as "polymer therapeutics", lies ahead.

Polymer therapeutics: polymers as drugs, drug and protein conjugates and gene delivery systems : Past, present and future opportunities

Abstract: As the 21st century begins we are witnessing a paradigm shift in medical practice. Whereas the use of polymers in biomedical materials applications - for example, as prostheses, medical devices, contact lenses, dental materials and pharmaceutical excipients - is long established, polymer-based medicines have only recently entered routine clinical practice [1-4]. Importantly, many of the innovative polymer-based therapeutics once dismissed as interesting but impractical scientific curiosities have now shown that they can satisfy the stringent requirements of industrial development and regulatory authority approval. The latter demand on one hand a cost-effective and profitable medicine or diagnostic, and on the other hand, a safe and efficacious profile that justifies administration to patients. The first clinical proof of concept with polymer therapeutics has coincided with the explosion of interest in the fashionable area called "nanotechnology". This has resulted in exponential growth in the field, and an increasing number of polymer chemists are turning their attention to the "bio-nano" arena. An attempt to define "nanotechnology" is beyond the scope of this review, but suffice it to say there is widespread agreement that application of nanotechnology to medicine, either via miniaturisation or synthetic polymer and supramolecular chemistry to construct nano-sized assemblies [5,6], offers a unique opportunity to design improved diagnostics, preventative medicines, and more efficacious treatments of life-threatening and debilitating diseases. It is thus timely for this volume of Advances in Polymer Science to review the field that has been named "polymer therapeutics" (Fig. 1). The term "polymer therapeutics" [1] has been adopted to encompass several families of constructs all using water-soluble polymers as components for design; polymeric drugs [3,7], polymer-drug conjugates [1,8], polymer-protein conjugates [2,9], polymeric micelles to which a drug is covalently bound [10], and those multi-component polyplexes being developed as non-viral vectors [11]. From an industrial standpoint, these nanosized medicines are more like new chemical entities than conventional "drug-delivery systems or formulations" which simply entrap, solubilise or control drug release without resorting to chemical conjugation. In this issue of Advances in Polymer Science, the current status of those technologies in preclinical and clinical development is reviewed, together with presentation of an emerging area of novel synthetic chemistry - the new field of polymer genomics - and also a description of some of the sophisticated analytical methods being developed to characterise complex polymer constructs.

Establishment of subcellular fractionation techniques to monitor the intracellular fate of polymer therapeutics I. Differential centrifugation fractionation B16F10 cells and use to study the intracellular fate of HPMA copolymer - doxorubicin.

Abstract: Polymer therapeutics are being designed for lysosomotropic, endosomotropic and transcellular drug delivery. Their appropriate intracellular routing is thus crucial for successful use. For example, polymer–anticancer drug conjugates susceptible to lysosomal enzyme degradation will never deliver their drug payload unless they encounter the appropriate activating enzymes. Many studies use confocal microscopy to monitor intracellular fate, but there is a pressing need for more quantitative methods able to define intracellular compartmentation over time. Only then will it be possible to optimise the next generation of polymer therapeutics for specific applications. The aim of this study was to establish a subcellular fractionation method for B16F10 murine melanoma cells and subsequently to use it to define the intracellular trafficking of N-(2-hydroxyproplylmethacrylamide) (HPMA) copolymer-bound doxorubicin (PK1). Free doxorubicin was used as a reference. The cell cracker method was used to achieve cell breaka...

Targeting and Intracellular Delivery of Drugs

Abstract: Effective targeting of drugs (particularly macromolecular therapeutics such as proteins, peptides, and oligonucleotides) to diseased cells, and moreover to the precise intracellular compartment where they are required has proved difficult to achieve. While the last decade has seen a number of drug delivery systems incorporating low molecular weight drugs and proteins enter routine clinical use, inadequate delivery is the single most important factor limiting our ability to utilize molecular medicines to their full potential. The body has evolved a number of very efficient biological barriers to protect itself from the harmful effects of pathogens (bacteria, viruses) and foreign materials such as proteins. These include environmental interfaces such as the gastrointestinal tract and the skin, internal cellular barriers such as the endothelial lining of blood vessels (particularly the tight blood–brain barrier), immune surveillance, and not least the cell membrane and inherent compartmentation of intracellular organelles. The current challenge is to design innovative devices and technologies (including nanomedicines) that will help guide the therapeutic to its correct location of action (drug targeting) and ensure that pharmacological activity is maintained for an adequate duration (controlled release). Keywords: Angiogenesis; Biomimetic Polymer; Controlled Release; Drug Targeting; Dendrimer; Endocytosis; Endosomotropic; Immunoconjugate; Liposome; Lysosomotropic; Micelle; Nanomedicines; Nanoparticle; Nanomedicine, the Discipline; Polymer Therapeutics; Polyplex

Polymer conjugates for drug targeting. From inspired to inspiration

Abstract: This special issue of the Journal of Drug Targeting is marking the past, and continuing contribution of Helmut Ringsdorf. Having witnessed for more than 30 years Helmut's never ending enthusiasm, p...

Polymer therapeutics : polymers as drugs, conjugates and gene delivery systems

Abstract: 1 R. Satchi-Fainaro, R. Duncan, C.M. Barnes: Polymer Therapeutics for Cancer: Current Status and Future Challenges.- 2 N. Nishiyama, K. Kataoka: Nanostructured Devices Based on Block Copolymer Assemblies for Drug Delivery: Designing Structures for Enhanced Drug Function.- 3 H. Maeda, K. Greish, J. Fang: The EPR Effect and Polymeric Drugs: A Paradigm Shift for Cancer Chemotherapy in the 21st Century.- 4 J.S. Ellis, S. Allen, Y.T. A. Chim, C.J. Roberts, S.J.B. Tendler, M.C. Davies: Molecular-Scale Studies on Biopolymers Using Atomic Force Microscopy.- 5 A.V. Kabanov, E.V. Batrakova, S. Sherman, V.Y. Alakhov: Polymer Genomics.-