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Multivalent self-assembled platforms for the delivery of chemotherapeutic drugs

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer.

Dr. Miriam Royo, who leads NANBIOSIS unit 3 of Synthesis of Peptide, explains one of the projects in which the ICTS is involved in relation with cancer therapy.

The improvement of solubility and stability of clinically approved chemotherapeutic drugs still represent a big challenge in cancer therapy. In fact, many of these drugs have low water solubility, which forces to administer larger volume doses to achieve the desired biological effect, and increases the side effects suffered from patients. The active principle can be chemically modified to increase the solubility, and administered as prodrug which, however, has to be enzymatically metabolized to have therapeutic effect and only a low percentage of the free drug is achieved. Moreover, some of the chemotherapeutic drugs are unstable at physiological conditions due to their chemical structure, and rapidly degrades before reaching the tumor tissue, further reducing the effectiveness of the treatment. Drugs commonly used in clinical chemotherapy treatments for advanced colorectal cancer and triple negative breast cancer, such as SN38, 5-fluorouracil (5-FU) and paclitaxel (PTX), have presented these problems, which affect their efficacy and tolerance to treatment by patients.

Drug delivery nanosystems based on biocompatible polyethylene glycol (PEG)-based multivalent platforms conjugated to hydrophobic drugs (SN38, PTX among others) are developed by the Multivalent Systems for Nanomedicine (MS4N) goup of Centro de Investigación Biom´dcia en Red (CIBER-BBN) at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC). The resulting water-soluble conjugates have also the ability to self-assemble in aqueous media in nanoscale micellar structures improving the pharmacokinetic profile of drugs. In these systems, the intact active principle can be released in a controlled manner thanks to the presence of degradable bonds, between the drug and the polymer, which are sensitive to chemical or biological stimuli, favoring its accumulation in tumor.

Systems containing only one drug (SN38 or PTX) for monotherapy and two different drugs (as SN38 and 5-FU) for combined therapy treatments are developed to improve the therapeutic efficacy of the free drugs and decrease their secondary effects.  The multivalence nature of these systems also allows the possibility to add targeting agents, such as tumor specific peptide ligands thus increasing the specificity of the platforms towards the cancer cells. These peptide ligands have been produced at the Synthesis of Peptides Unit (U3) of NANBIOSIS.

This project (RTI2018-093831-B-I00) is funded by MICIN/AEI/10.13039/501100011033 and by “ERDF A way to of making Europe and performed in collaboration with Dr. Ibane Abasolo group of CIBER-BBN at Vall d’Hebron Research Institute (VHIR) and the In Vivo Experimental Platform (U20) of NANBIOSIS under the frame of CIBER BBN intramural collaborative projects (PolyPlaTher, Colocomb and Nanomets).

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NANBIOSIS research to fight cancer

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer. Some examples of the work carried out during the last year, are bellow:

Unit 20 of NANBIOSIS  at VHIR, works in several proyects reletaed to cancer as  H2020-NoCanTher: magnetic nanoparticles against pancreatic cancer through the use of hyperthermia combined with conventional treatment. H2020-Target-4-Cancer: nanotherapy based on polymeric micelles directed against specific receptors of tumor stem cells in colorectal cancer. H2020-DiamStar: nanodiamonds directed against leukemia for the potentiation of chemotherapy. FET-OPEN EvoNano: in silico and tumor-tumor models for the prediction of PK / PD and tumor efficacy of antitumor nanomedicines against tumor stem cells.

The activities of U1 of Protein Production Platform (PPP) are also strongly committed with several projects devoted to develop new, more selective and more efficient antitumoral drugs, with antimetastatic effects.
oordinated action between units U1 of Protein Production Platform (PPP),
U18 of Nanotoxicology and U29 of Nucleic Acid Synthesis, shows promising results in development of nanopharmaceuticals with a high degree of efficacy for the treatment of metastases in colon cancer

Unit 6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit  is also working on a joined initiative between CIBER-BBN and CIBER-ONC to improve the current ex vivo immune cell expansion systems to help introduce immunotherapies such as the adoptive cell therapies, which have shown complete remissions of terminal cancer patients, to the clinics overcoming the limitation of having enough therapeutic cells with novel Nanobiomaterials. Researchers of Unit 6 and researchers of Laboratory of Translational Research in Child and Adolescent Cancer from the Vall d’Hebron Research Institute (VHIR), are working on a project financed by the Spanish Government and CIBER-BBN, for the development of a new nanomedicine for the treatment of high-risk neuroblastoma, one of the most frequent childhood cancers.

In our unit U26. NMR: Biomedical Applications II,  several studies for cancer biomarker discovery are being carried out. NMR studies on biofluids for the design of novel strategies for diagnosis support, easily transferable into the clinical practice, are being developed in biofluids in the context of cancer. Urine is one of the most easily obtainable biofluid and is a non-invasive source of biomarkers. Among these studies, we can mention the good discrimination achieved between urine from bladder cancer patients before surgery (cancer) and urine after surgery (free of cancer) and in the follow up of the disease, to monitor relapses

Some of the results of these researchs have been published in scientific magazines of high impact as for exemple;

Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer Alba Loras, Cristian Suárez-Cabrera, M. Carmen Martínez-Bisbal, Guillermo Quintás , Jesús M. Paramio, Ramón Martínez-Máñez,
Salvador Gil and José Luis Ruiz-Cerdá. Cancers 2019, 11, 686; doi:10.3390/cancers11050686

Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells Naroa Serna, Patricia Álamo, Prashanthi Rameshef, Daria Vinokurovaef, LauraSánchez-García, Ugutz Unzueta, Alberto Gallardo, María  Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. . Journal of Controlled Release.  Volume 320, 96-104, 2020 https://doi.org/10.1016/j.jconrel.2020.01.019

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering Voltà-Durán, E., Cano-Garrido, O., Serna, N. et al. C. Sci. China Mater.63, 147–156 (2020). https://doi.org/10.1007/s40843-019-9582-9

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci, María Virtudes Céspedes  Olivia Cano‐Garrido  Patricia Álamo  Rita Sala  Alberto Gallardo  Naroa Serna  Aïda Falgàs  Eric Voltà‐Durán  Isolda Casanova  Alejandro Sánchez‐Chardi  Hèctor López‐Laguna  Laura Sánchez‐García  Julieta M. Sánchez  Ugutz Unzueta  Esther Vázquez  Ramón Mangues  Antonio Villaverde . Advanced Materiasls Número de artículo: 1907348 , Dec. 2019 https://doi.org/10.1002/adma.201907348

Artificial Inclusion Bodies for Clinical Development Julieta M. Sánchez  Hèctor López‐Laguna  Patricia Álamo  Naroa Serna  Alejandro Sánchez‐Chardi  Verónica Nolan  Olivia Cano‐Garrido  Isolda Casanova  Ugutz Unzueta  Esther Vazquez  Ramon Mangues  Antonio Villaverde, Advanced Science. 2019 https://doi.org/10.1002/advs.201902420

Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells Mireia Pesarrodona, Laura Sánchez-García, Joaquin Seras-Franzoso, Alejandro Sánchez-Chardi, Ricardo Baltá-Foix, Patricia Cámara-Sánchez, Petra Gener,  José Juan Jara, Daniel Pulido, Naroa Serna, Simó Schwartz Jr. Miriam Royo, Antonio Villaverde, Ibane Abasolo, Esther Vazquez ACS Applied Materials & Interfaces DOI: 10.1021/acsami.9b15803  

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery López‐Laguna, H., Sala, R., Sánchez, J. M., Álamo, P., Unzueta, U., Sánchez‐Chardi, A., Serna, N., Sánchez‐García, L., Voltà‐Durán, E., Mangues, R., Villaverde, A., Vázquez, E., . Part. Part. Syst. Charact. 2019, 36, 1900304. https://doi.org/10.1002/ppsc.201900304

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Polyurethane and polyurea nanoparticle (PUUa), improves cancer therapy

The national consortium led by the research group of Addressing and Drug Release CIBBIM – Nanomedicine of the Vall d’Hebron Research Institute (VHIR) and led by Dr. Ibane Abasolo, Scientific Coordinataror of Unit 20 of NANBIOSIS, has shown improvement in the effectiveness and specificity of targeted therapy against cancer through the use of polyurethane-polyurea nanocapsules (PUUa), a nanoparticle with a proven targeted release, very useful for drugs with a high level of toxicity and low specificity of distribution. This nanoparticle has been developed by the research section of the Catalan company EcopolTech and Unit 20 of ICTS Nanbiosis has participated in vivo nanoparticle biodistribution assays, following the tissue accumulations of fluorescently labeled nanoparticles by means of the IVIS-Spectrum equipment. 

The study was based on the encapsulation of the drug Plitidepsin produced and patented by the Spanish pharmaceutical company PharmaMar SA. This drug, which was found in a marine invertebrate of Mediterranean origin and has proven efficacy in laboratory studies, also has a hydrophobic nature that makes its use in humans difficult. The nanoparticle PUUa, by covering the drug, improves biodistribution and reduces the toxicity of the drug, in addition to dramatically reducing the concentration necessary for its therapeutic function. Thus, it potentially increases the use of Plitidepsin in therapy for several types of cancer.
The nanocapsule is based on a shell made of, an RGD peptide to direct the nanoparticles to tumor cells and other fractions that ensure that the drug is released in environments with a high content of glutathione, a molecule that is found in high concentrations inside the tumor cells. Once inside the cell, the drug content is released and therapeutic function begins, highly effective in glioblastoma, colorectal cancer and breast cancer.

The research and synthesis of this nanocapsule has been carried out in collaboration with the Biomedical Research Institute, the CIBBER-BBN, and the companies Ecopol Tech SL and PharmaMar SA.

The importance of nanomedicine in cancer therapy:
In nanomedicine, a nanocapsule refers to an organic and biodegradable nanometric container that contains other molecules inside it, to be released once they reach their destination. In the case of cancer treatment, nanocapsules contain drugs that are usually hydrophobic and if they are administered naked (or without being wrapped by the nanocapsule), they are vulnerable to detection and digestion by macrophages – which reduces the effective accumulation of the drug in the tumor cells-, in addition to presenting a high toxicity both for the tumor cells of interest and for the healthy cells of the individual. These immunological barriers cause the administration at high concentrations of the drug chosen for the therapy, which leads to the known side effects of chemotherapy and the appearance of resistance.

Encapsulation can solve these problems: it prevents the elimination of drugs by macrophages, they circulate for a longer time through the blood flow, and they have improved permeability and retention. All because they are more specific covers and less toxic to the human body. Some of these nanomedicines are already being used in oncological patients, such as Myocet ™, DaunoXome ™, Depocyt ™, Abraxane ™, Genexol- * PM ™, and more recently, Onivyde ™: and all have improved the survival of cancer patients in a significative way.

And the research goes further, since the CIBBIM – Nanomedicine Pharmacological Surveillance and Release group of the VHIR has been working for ten years to bring the nanomedicines in development closer to patients and is currently working on several European projects in which several studies are being studied. nanoparticles for the treatment of pancreatic cancer, colorectal and breast cancer, Ewing sarcoma and Fabry minority disease.

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