Review Articles

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Rodriguez‐Otormin, F.,  Duro‐Castaño, A., Conejos‐Sánchez, I., Vicent, M.J. Envisioning the Future of Polymer Therapeutics for Brain Disorders. WIREs Nanomedicine and Nanobiotechnology, 2018;e1532. [PubMed][Journal Website][Zenodo][Advanced Science News]

The growing incidence of brain‐related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro‐related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from “bench to bedside” for various biomedical applications. However, since the approval of Gliadel® wafers, little progress has been made in the CNS field, even though brain targeting represents an ever‐growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease‐specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders.

Atkinson, S.P., Andreu, Z., and Vicent, M.J., Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment. Journal of Personalized Medicine, 2018. 8(1): p. 6. [PubMed][Free Download at JPM][Zenodo]

Polymer therapeutics (PTs) provides a potentially exciting approach for the treatment of many diseases by enhancing aqueous solubility and altering drug pharmacokinetics at both the whole organism and subcellular level leading to improved therapeutic outcomes. However, the failure of many polymer-drug conjugates in clinical trials suggests that we may need to stratify patients in order to match each patient to the right PT. In this concise review, we hope to assess potential PT-specific biomarkers for cancer treatment, with a focus on new studies, detection methods, new models and the opportunities this knowledge will bring for the development of novel PT-based anti-cancer strategies. We discuss the various “hurdles” that a given PT faces on its passage from the syringe to the tumor (and beyond), including the passage through the bloodstream, tumor targeting, tumor uptake and the intracellular release of the active agent. However, we also discuss other relevant concepts and new considerations in the field, which we hope will provide new insight into the possible applications of PT-related biomarkers.

Satchi-Fainaro, R., Vicent, M.J., and Richardson, S., Professor Ruth Duncan: A Pioneer in the Field of Polymer Therapeutics. Journal of Drug Targeting, 2017: p. 1-3. [PubMed]

Editorial: This special issue of the Journal of Drug Targeting marks the past, and the continuing contribution of Ruth Duncan to the field of drug delivery, more specifically the branch termed “Polymer Therapeutics”. The three of us have witnessed, for more than 20 years, Ruth’s never-ending enthusiasm and persistence in many different interdisciplinary arenas under this banner, and the immense scientific contribution to the field of drug delivery this vision (and tenacity) has generated. It has been a pleasure for us to edit this special issue, which pays tribute to her outstanding achievements within the context of the Journal of Drug Targeting- Lifetime Achievement Award for 2017.

Duro-Castano, A., Gallon, E., Decker, C., and Vicent, M.J.*, Modulating angiogenesis with integrin-targeted nanomedicines. Advanced Drug Delivery Reviews, 2017. 119(Supplement C): p. 101-119.[PubMed] [Zenodo]

Targeting angiogenesis-related pathologies, which include tumorigenesis and metastatic processes, has become an attractive strategy for the development of efficient guided nanomedicines. In this respect, integrins are cell-adhesion molecules involved in angiogenesis signaling pathways and are overexpressed in many angiogenic processes. Therefore, they represent specific biomarkers not only to monitor disease progression but also to rationally design targeted nanomedicines. Arginine-glycine-aspartic (RGD) containing peptides that bind to specific integrins have been widely utilized to provide ligand-mediated targeting capabilities to small molecules, peptides, proteins, and antibodies, as well as to drug/imaging agent-containing nanomedicines, with the final aim of maximizing their therapeutic index. Within this review, we aim to cover recent and relevant examples of different integrin-assisted nanosystems including polymeric nanoconstructs, liposomes, and inorganic nanoparticles applied in drug/gene therapy as well as imaging and theranostics. We will also critically address the overall benefits of integrin-targeting.

Cheah, H.Y., Kiew, L.V., Lee, H.B., Japundžić-Žigon, N., Vicent, M.J., Hoe, S.Z., and Chung, L.Y., Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry. Journal of Applied Toxicology, 2017. 37(11): p. 1268-1285. [PubMed

While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS.

Zagorodko, O., Arroyo-Crespo, J.J., Nebot, V.J., and Vicent, M.J.*, Polypeptide-Based Conjugates as Therapeutics: Opportunities and Challenges. Macromol Biosci, 2017. 17(1). [PubMed] [Zenodo]

Synthetic polypeptides or polyamino acids have become a useful and multifunctional platform in advanced drug delivery studies. Nonetheless, the full potential of these systems has yet to be achieved. The final structure of polypeptide conjugates and their in vivo behavior are dependent on an extraordinarily complex pattern of interconnected physico-chemical and structural parameters, making sophisticated directional design of such systems difficult and often unachievable. In this review, the authors aim to discuss the role of these parameters in the successful design of different drug delivery architectures and to delineate some basic correlations between structure, properties, and the biological behavior of polypeptide-based conjugates.

This review article was one of the journal’s top 20 most downloaded recent papers among articles published between July 2016 and June 2018.

Nino-Pariente, A., Nebot, V.J., and Vicent, M.J.*, Relevant Physicochemical Descriptors of “Soft Nanomedicines” to Bypass Biological Barriers. Curr Pharm Des, 2016. 22(9): p. 1274-91. [PubMed] [Zenodo]

Herein, we present an overview on the current status of the characterization techniques and methodologies used to study the physicochemical descriptors that influence the final clinical performance of a given nanomedicine. The described techniques were selected based on their suitability to operate under relevant “native” conditions that mimic the physiological environment. Special emphasis is placed on those techniques that hold a greater potential to unravel dynamic, structural, and compositional features of soft organic nanomedicines relevant to the ability to bypass biological barriers, and hence allow for the rational design of drug delivery platforms with improved biological output.

Duro-Castano, A., Movellan, J., and Vicent, M.J.*, Smart branched polymer drug conjugates as nano-sized drug delivery systems. Biomater Sci, 2015. 3(10): p. 1321-34. [PubMed

Polymer-drug conjugates represent excellent nanopharmaceutical candidates, as they offer multiple advantages related to their intrinsic characteristics. Many of the said characteristics are provided by the covalent bonding between the drug and the polymer. However, their clinical development has been slow and only one polymer-drug conjugate has reached the market, thus there remains an urgent need for the development of new and smart polymeric systems. Desirable characteristics of these new systems include higher molecular weight and degree of homogeneity, predictable conformations in solution, multivalency, and increased drug loading capacity, amongst others. With these aims in mind, branched polymers are ideal candidates due to their unique rheological, mechanical, and biomedical properties derived from their structure, inaccessible for linear polymers. Within this review, the synthetic strategies developed and the main efforts towards branched polymer implementation as carriers for polymer-drug conjugates will be addressed.

Duro-Castano, A., Conejos-Sánchez, I., and Vicent, M.J.*, Peptide-Based Polymer Therapeutics. Polymers, 2014. 6(2): p. 515. [Link

Polypeptides are envisaged to achieve a major impact on a number of different relevant areas such as biomedicine and biotechnology. Acquired knowledge and the increasing interest on amino acids, peptides and proteins is establishing a large panel of these biopolymers whose physical, chemical and biological properties are ruled by their controlled sequences and composition. Polymer therapeutics has helped to establish these polypeptide-based constructs as polymeric nanomedicines for different applications, such as disease treatment and diagnostics. Herein, we provide an overview of the advantages of these systems and the main methodologies for their synthesis, highlighting the different polypeptide architectures and the current research towards clinical applications.

Duncan, R. and Vicent, M.J.*, Polymer therapeutics-prospects for 21st century: the end of the beginning. Adv Drug Deliv Rev, 2013. 65(1): p. 60-70. [PubMed

The term “polymer therapeutics” was coined to describe polymeric drugs, polymer conjugates of proteins, drugs and aptamers, together with those block copolymer micelles and multicomponent non-viral vectors which contain covalent linkages. These often complex, multicomponent constructs are actually “drugs” and “macromolecular prodrugs” in contrast to drug delivery systems that simply entrap (non-covalently) therapeutic agents. They have also been described as nanomedicines. First polymer-protein conjugates entered routine clinical use in 1990 and a growing number of polymeric drugs/sequestrants and PEGylated proteins/aptamers have since come into the market. Valuable lessons have been learnt over >3 decades of clinical development, especially in relation to critical product attributes governing safety and efficacy, the validated methods needed for product characterisation. Not least there has been improved understanding of polymer therapeutic-specific biomarkers that will in future enable improved selection of patients for therapy. Advances in synthetic polymer chemistry (including control of 3D architecture), the move towards greater use of biodegradable polymers, polymers delivering combination therapy, increased understanding of polymer therapeutic critical product attributes to guide pharmaceutical development, and advances in understanding of endocytosis and intracellular trafficking pathways in health and disease are opening new opportunities for design and clinical use of polymer-based therapeutics in the decades to come.

Perez-Paya, E., Orzaez, M., Mondragon, L., Wolan, D., Wells, J.A., Messeguer, A., and Vicent, M.J.*, Molecules that modulate Apaf-1 activity. Med Res Rev, 2011. 31(4): p. 649-75. [PubMed

Programmed cell death, apoptosis, is a highly regulated cellular pathway, responsible for the elimination of cells in the organism that are no longer needed or extensively damaged. Defects in the regulation of apoptosis could be at the molecular basis of different diseases, either when it is insufficient or excessive. The formation of the macromolecular complex, apoptosome, is a key event in this pathway, which has also been defined as the intrinsic apoptosis pathway. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated apoptotic protease-activating factor (Apaf-1), dATP, and procaspase-9. Recent studies have produced a wealth of information about the regulation and functions of Apaf-1, but additional studies aimed at elucidating its role as a signaling device at the crosstalk between different signaling pathways are needed to take advantage for the development of modulators of apoptosis pathways and possible therapeutic applications.

Barz, M., Luxenhofer, R., Zentel, R., and Vicent, M.J.*, Overcoming the PEG-addiction: well-defined alternatives to PEG, from structure-property relationships to better defined therapeutics. Polymer Chemistry, 2011. 2(9): p. 1900-1918. [Link

Synthetic methods in polymer chemistry have evolved tremendously during the last decade. Nowadays more and more attention is devoted to the application of those tools in the development of the next generation of nanomedicines. Nevertheless, poly(ethylene glycol) (PEG) remains the most frequently used polymer for biomedical applications. In this review, we try to summarize recent efforts and developments in controlled polymerisation techniques that may allow alternatives to PEG based systems and can be used to improve the properties of future polymer therapeutics. [Journal Website]

Canal, F., Sanchis, J., and Vicent, M.J.*, Polymer–drug conjugates as nano-sized medicines. Curr Opin Biotechnol, 2011. 22(6): p. 894-900. [PubMed

Polymer Therapeutics have enormously evolved in the past decades. Several polymeric drugs as well as polymer-protein conjugates have been in the market since the 90s, but although polymer-drug conjugates are already in clinical trials they still need to reach this final goal. There are four main convergent strategies to move this platform technology further. First, exploitation of new molecular targets in cancer therapy and design of polymer-drug conjugates as treatments for other diseases. Second, the development of combination therapy. Third, attempts to improve polymer chemistry, including the use of new well-defined architectures and the optimization of the advanced characterization techniques essential to transform a promising conjugate into a candidate for clinical evaluation. Finally, increased understanding of polymer conjugate features that govern clinical risk-benefit is leading to an appreciation of clinical biomarkers that will open new possibilities for personalized therapy.

Sanchis, J., Canal, F., Lucas, R., and Vicent, M.J.*, Polymer-drug conjugates for novel molecular targets. Nanomedicine (Lond), 2010. 5(6): p. 915-35. [PubMed

Polymer therapeutics can be already considered as a promising field in the human healthcare context. The discovery of the enhanced permeability and retention effect by Maeda, together with the modular model for the polymer-drug conjugate proposed by Ringsdorf, directed the early steps of polymer therapeutics towards cancer therapy. Orthodox anticancer drugs were preferentially chosen in the development of the first conjugates. The fast evolution of polymer chemistry and bioconjugation techniques, and a deeper understanding of cell biology has opened up exciting new challenges and opportunities. Four main directions have to be considered to develop this ‘platform technology’ further: the control of the synthetic process, the exhaustive characterization of the conjugate architectures, the conquest of combination therapy and the disclosure of new therapeutic targets. We illustrate in this article the exciting approaches offered by polymer-drug conjugates beyond classical cancer therapy, focusing on new, more effective and selective targets in cancer and in their use as treatments for other major human diseases.

Duncan, R. and Vicent, M.J.*, Do HPMA copolymer conjugates have a future as clinically useful nanomedicines? A critical overview of current status and future opportunities. Adv Drug Deliv Rev, 2010. 62(2): p. 272-82. [PubMed

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing doxorubicin designed in the late 1970s/early 1980s as anticancer polymer therapeutics were the first synthetic polymer-based anticancer conjugates to enter clinical trial beginning in 1994. Early clinical results were promising, confirming activity in chemotherapy refractory patients and the safety of HPMA copolymers as a new polymer platform in this setting. Subsequent Phase I/II trials have investigated conjugates containing paclitaxel (PNU 166945), camptothecin (PNU 166148) (both failed in clinical trials underlining the importance of rational design), and most recently HPMA-copolymer platinates (AP5280 and then AP5346-ProLindac(TM)) entered Phase II clinical development. There are a growing array of second generation HPMA copolymer-based systems involving combination therapy, incorporating putative targeting ligands, having an ever more complex architecture, and both drug and protein conjugates are being proposed as novel treatments for diseases other than cancer. Despite their promise, and the success of polymeric drugs and polymer-protein conjugates, no polymer-drug conjugate (HPMA copolymer-based or otherwise) has yet entered routine clinical use. It is timely to reflect on the progress made over the last 30 years, the relative merits of HPMA copolymers as a platform compared to other polymeric carriers, and comment on their future potential as polymer-based nanomedicines into the 21st century in comparison with the many alternative strategies now emerging for creation of nanopharmaceuticals.

Greco, F. and Vicent, M.J.*, Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev, 2009. 61(13): p. 1203-13. [PubMed]

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer-drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.

Vicent, M.J.*, Ringsdorf, H., and Duncan, R., Polymer therapeutics: clinical applications and challenges for development. Adv Drug Deliv Rev, 2009. 61(13): p. 1117-20. [PubMed

This preface is part of the Advanced Drug Delivery Reviews theme issue on “Polymer Therapeutics: Clinical Applications and Challenges for Development”.

 

 

 

Vicent, M.J., Dieudonne, L., Carbajo, R.J., and Pineda-Lucena, A., Polymer conjugates as therapeutics: future trends, challenges and opportunities. Expert Opin Drug Deliv, 2008. 5(5): p. 593-614. [PubMed

Clinical proof of concept for polymer conjugates has already been achieved over the last 30 years, with a family of polymer-protein conjugates reaching the market and an exponentially growing list of polymer-drug conjugates currently in clinical trials. However, many challenges and opportunities still lie ahead, providing scope to develop this platform technology further. METHODS: The delivery of new anticancer agents aimed at novel molecular targets and their combination, the development of both new polymeric materials with defined architectures and the treatment of diseases other than cancer are the most exciting and promising areas. The latest advances and future trends in the polymer conjugate field will be presented in this article, providing an insight into their potential in the clinics and offering a wide range of research approaches within the scientific community. RESULTS/CONCLUSION: Polymer therapeutics is a rapidly emerging field with exponentially growing opportunities to achieve medical treatments with highly enhanced therapeutic value.

Greco, F. and Vicent, M.J.*, Polymer-drug conjugates: current status and future trends. Front Biosci, 2008. 13: p. 2744-56. [PubMed]  

Polymer conjugates are nano-sized, multi-component constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The ”technology platform” of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these “nanomedicines”.

Vicent, M.J., Perez-Paya, E., and Orzaez, M., Discovery of inhibitors of protein-protein interactions from combinatorial libraries. Curr Top Med Chem, 2007. 7(1): p. 83-95. [PubMed

Protein-protein interactions play a central role within numerous processes in the cell. The relevance of the processes in which this type of interactions are implicated make them responsible for many pathological situations. In the last decade protein-protein interfaces have shown their potential as new drug targets, and combinatorial chemistry has been defined as a useful tool in this line. This review gives a global vision of the actual situation of combinatorial chemistry, highlighting its applicability to high-throughput drug discovery and giving some crucial examples of its contribution to find modulators of protein-protein interactions.

Vicent, M.J.*, Polymer-drug conjugates as modulators of cellular apoptosis. AAPS J, 2007. 9(2): p. E200-7. [PubMed

The successful clinical application of polymer-protein conjugates (PEGylated enzymes and cytokines) and the promising results arising from clinical trials with polymer-bound chemotherapy (eg, doxorubicin or paclitaxel) have established their potential to reduce toxicity and improve activity in chemotherapy-refractory patients. Furthermore, and more important, they have also provided a firm foundation for more sophisticated second-generation constructs that deliver the newly emerging target-directed bioactive agents (eg, modulators of apoptosis, cell cycle, anti-angiogenic drugs) in addition to polymer-based drug combinations (eg, endocrine therapy and chemotherapy). This review will focus on polymer-drug conjugate modulators of cellular apoptosis to be used as single pro-apoptotic (eg, cancer) or anti-apoptotic (eg, ischemia) agents or as a combination therapy.

Orzáez, M., Mora, P., Mondragón, L., Pérez-Payá, E., and Vicent, M.J.*, Solid-phase Chemistry: A Useful Tool to Discover Modulators of Protein Interactions. International Journal of Peptide Research and Therapeutics, 2007. 13(1): p. 281-293. [Link

The Solid phase synthesis (SPS) concept, first developed for biopolymers, has spread in every field where organic synthesis is involved. While the potential of the solid-phase method was obvious in 1959 to its discoverer, Prof. R. B. Merrifield, it was unpredictable its dominance in peptide synthesis and especially in combinatorial chemistry, an area not yet conceived. SPS paved the way for solid-phase combinatorial approaches as many laboratories and companies focused on the development of technologies and chemistry suitable to this new methodology. This resulted in the spectacular outburst of combinatorial chemistry, which profoundly changed the approach for new drug discovery. Combinatorial chemistry is currently considered a valid approach for a wide range of biomedical applications, such as, target validation and drug discovery.

Vicent, M.J.* and Duncan, R., Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol, 2006. 24(1): p. 39-47. [PubMed

Interdisciplinary research at the interface of polymer chemistry and the biomedical sciences has produced the first polymer-based nanomedicines for the diagnosis and treatment of cancer. These water-soluble hybrid constructs, designed for intravenous administration, fall into two main categories: polymer-protein conjugates or polymer-drug conjugates. Polymer conjugation to proteins reduces immunogenicity, prolongs plasma half-life and enhances protein stability. Polymer-drug conjugation promotes tumor targeting through the enhanced permeability and retention (EPR) effect and, at the cellular level following endocytic capture, allows lysosomotropic drug delivery. The successful clinical application of polymer-protein conjugates (PEGylated enzymes and cytokines) and promising results arising from clinical trials with polymer-bound chemotherapy (e.g. doxorubicin, paclitaxel, camptothecins) has provided a firm foundation for more sophisticated second-generation constructs that deliver the newly emerging target-directed anticancer agents (e.g. modulators of the cell cycle, signal transduction inhibitors and antiangiogenic drugs) in addition to polymer-drug combinations (e.g. endocrine- and chemo-therapy).

Duncan, R., Vicent, M.J., Greco, F., and Nicholson, R.I., Polymer-drug conjugates: towards a novel approach for the treatment of endocrine-related cancer. Endocr Relat Cancer, 2005. 12 Suppl 1: p. S189-99. [PubMed

The last decade has seen successful clinical application of polymer-protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer-anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80-320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Altava, B., Burguete, M.I., Garcı́a-Verdugo, E., Luis, S.V., Vicent, M.J., and Mayoral, J.A., Supported chiral catalysts: the role of the polymeric network. Reactive and Functional Polymers, 2001. 48(1–3): p. 25-35. [Link

In the preparation of chiral-supported catalysts, the immobilization process can produce changes in the behavior of the resulting resin-supported species. The polymeric matrix plays important roles that affect the activity, selectivity and stability of the final catalysts. Pseudodilution effects very often favor the activity of the supported species, and the presence of the hydrophobic matrix increases the stability of the water-sensitive active sites. The steric interaction between the polymeric backbone and the groups in the chiral auxiliary can modify, even dramatically, the stereochemical outcome of the reaction.