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Arroyo-Crespo, J.J., Armiñán, A., Charbonnier, D., Balzano-Nogueira, L., Huertas-López, F., Martí, C., Tarazona, S., Forteza, J., Conesa, A., Vicent, M.J*. Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment. Biomaterials, 2018. 186: p8-21. [PubMed][Free Download at Biomaterials].
The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of –omics-based analysis to accelerate anticancer DDS.
Arroyo‐Crespo, J.J., Deladriere, C., Nebot, V.J., Charbonnier, D., Masiá, E., Paul, A., James, C., Armiñán, A.*, and Vicent, M.J.*, Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid‐Based Combination‐Drug Conjugate. Advanced Functional Materials, 2018. 28(22): p. 1800931 [See Full text free at Advanced Functional Materials][Zenodo]
Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer-drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer-drug conjugates at the supramolecular level to allow the design of more effective polymer-drug conjugates.
Armiñán, A., Palomino-Schätzlein, M., Deladriere, C., Arroyo-Crespo, J. J., Vicente-Ruiz, S., Vicent, M. J.*, and Pineda-Lucena, A.* Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models. Biomaterials, 2018. 162: p144-153. [PubMed][Zenodo][Download PDF free at Biomaterials]
Metabolomics is becoming a relevant tool for understanding the molecular mechanisms involved in the response to new drug delivery systems. The applicability of this experimental approach to cell cultures and animal models makes metabolomics a useful tool for establishing direct connections between in vitro and in vivo data, thus providing a reliable platform for the characterization of chemotherapeutic agents. Herein, we used metabolomic profiles based on nuclear magnetic resonance (NMR) spectroscopy to evaluate the biochemical pathways involved in the response to a chemotherapeutic anthracycline drug (Doxorubicin, Dox) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-conjugated form (HPMA-Dox) in an in vitro cell culture model and an in vivo orthotopic breast cancer model. We also used protein expression and flow cytometry studies to obtain a better coverage of the biochemical alterations associated with the administration of these compounds. The overall analysis revealed that polymer conjugation leads to increased apoptosis, reduced glycolysis, and reduced levels of phospholipids when compared to the free chemotherapeutic drug. Our results represent a first step in the application of integrated in vitro and in vivo metabolomic studies to the evaluation of drug delivery systems.
Duro-Castaño, A., Nebot, V. J., Niño-Pariente, A., Armiñán, A., Arroyo-Crespo, J. J., Paul, A., Feiner-Gracia, N., Albertazzi, L. and Vicent, M. J.* Capturing “Extraordinary” Soft-Assembled Charge-Like Polypeptides as a Strategy for Nanocarrier Design. Adv Mater, 2017. 29(39): p. 1702888-n/a. [PubMed] [Zenodo][Download PDF free at Advanced Materials]
The rational design of nanomedicines is a challenging task given the complex architectures required for the construction of nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Herein, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in nonsalty aqueous solutions is identified, which matches the ubiquitous “ordinary-extraordinary” phenomenon previously described by physicists. For the first time, a bottom-up methodology for the stabilization of these nanosized soft-assembled star-shaped polyglutamates is also described, enabling the translation of theoretical research into nanomaterials with applicability within the drug-delivery field. Covalent capture of these labile assemblies provides access to unprecedented architectures to be used as nanocarriers. The enhanced in vitro and in vivo properties of these novel nanoconstructs as drug-delivery systems highlight the potential of this approach for tumor-localized as well as lymphotropic delivery.
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. In Press. [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 PDF Download at JPM][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.
Zagorodko, O., J. J. Arroyo-Crespo, V. J. Nebot and M. J. Vicent (2016). Polypeptide-Based Conjugates as Therapeutics: Opportunities and Challenges. Macromolecular Bioscience. 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.
Niño-Pariente, A., Nebot, V. J. and Vicent, M. J. (2016). Relevant Physicochemical Descriptors of “Soft Nanomedicines” to Bypass Biological Barriers. Current Pharmaceutical Design 22(9): 1274-1291. [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.
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.
PCT application number PCT/EP2016/067554
Title CROSS-LINKED STAR-SHAPED SELF-ASSEMBLED POLYPEPTIDES AND ITS USE AS CARRIERS IN BIOMEDICAL APPLICATIONS
AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL, USA – Abstract 3726: Design of personalised polymer based combination therapeutics for advanced stage breast cancer patients [Link]
NanoBio&Med 2018 November 20 – 22, Barcelona (Spain): Targeting Tumor Microenvironment with Rationally Designed Polypeptide-based Conjugates [PDF]