Pablo Scodeller
Ramón y Cajal Researcher
Research summary
Targeting peptides can be used to carry relevant cargo to specific tissue or cells in the disease, to improve treatment and diagnosis. Targeting peptides provide selectivity, versatility, deep tissue penetration, low immunogenicity and ease and low cost of synthesis. The aim of the Peptide-Guided Theranostics Lab is to identify new targeting peptides and perform precision delivery for cancer, immunomodulation, and Alzheimer’s disease, by designing peptide-guided theranostics that can be translated to the clinic.
Publications
A Lepland, A Malfanti, U Haljasorg, E K. Asciutto, M Pickholz, M Bringas, S Đorđević, L Salumäe, P Peterson, T Teesalu, MJ Vicent, P Scodeller. Depletion of Mannose Receptor-Positive Tumor-Associated Macrophages via a Peptide-Targeted Star-Shaped Polyglutamate Inhibits Breast Cancer Progression in Mice. Cancer Research Communications 2022; crcres.0043.2022.
Lepland A, Asciutto EK, Malfanti A, Simón-Gracia L, Sidorenko V, Vicent MJ, Teesalu T, Scodeller P. Targeting Pro-Tumoral Macrophages in Early Primary and Metastatic Breast Tumors with the CD206-Binding mUNO Peptide. Mol Pharm. 2020 Jul 6;17(7):2518-2531.
Asciutto EK, Kopanchuk S, Lepland A, Simón-Gracia L, Aleman C, Teesalu T, Scodeller P. Phage-Display-Derived Peptide Binds to Human CD206 and Modeling Reveals a New Binding Site on the Receptor. J Phys Chem B. 2019 Mar 7;123(9):1973-1982.
Scodeller P, Asciutto EK. Targeting Tumors Using Peptides. Molecules. 2020 Feb 13;25(4):808.
Figueiredo P, Lepland A, Scodeller P, Fontana F, Torrieri G, Tiboni M, Shahbazi MA, Casettari L, Kostiainen MA, Hirvonen J, Teesalu T, Santos HA. Peptide-guided resiquimod-loaded lignin nanoparticles convert tumor-associated macrophages from M2 to M1 phenotype for enhanced chemotherapy. Acta Biomater. 2021 Oct 1;133:231-243.
Ewert KK, Scodeller P, Simón-Gracia L, Steffes VM, Wonder EA, Teesalu T, Safinya CR. Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics. Pharmaceutics. 2021 Aug 30;13(9):1365.
Funding
PID2021-122364OA-I00, Photo-Immunomodulation in Glioblastoma Using Photosensitizer-Peptide Conjugates (PIMPEP). Spanish Ministry of Science (MICINN). Plan Nacional grant.
R21-6405053838, Pro-tumoral macrophage depletion using peptide-drug conjugates and photodynamic therapy. Royal Society of Chemistry (RSC) Research Fund Grant.
Tumor associated macrophages (TAMs)
Cancer cells “corrupt” macrophages into adopting an anti-inflammatory phenotype that favors tumor progression, metastasis and resistance to chemo and immunotherapies. We are interested in devising pharmacologically relevant strategies to intervene on the “right” subset of pro-tumoral macrophages while sparing the inflammatory (tumoricidal) macrophages. In this direction, in 2017 (Scodeller et al. Sci. Rep 2017), using in vivo peptide phage display in mice bearing metastatic breast cancer, we identified a short peptide designated “mUNO” that targets pro-tumoral macrophages by binding to CD206 (mannose receptor).
We are focused on TAM depletion and reprogramming to attenuate resistance to therapies and metastasis in solid tumors. We recently designed an mUNO targeted compound to deplete macrophages in triple negative breast tumors in mice. The mUNO-guided, doxorubicin (DOX)-carrying polymer drug conjugate, designated “OximUNO”, depleted CD206+ macrophages in different metastatic breast cancer models, relieved immunosuppression, and provided higher efficacy and lower side effects than a conventional chemotherapy (Figure 1).
Figure 1. Peptide-guided TAM depletion in breast cancer using “OximUNO”. Collaboration with the MJ Vicent Lab (CIPF, Valencia, Spain) Reference: https://www.biorxiv.org/content/10.1101/2021.12.29.474487v2
To expand the translational applications of our targeting peptides, we recently engineered an improved version of the mUNO targeting peptide, designated “TrimUNO”, that has higher proteolytic resistance and is able to target TAMs by oral administration (Figure 2). Forthcoming steps will include oral delivery of TAM-aimed therapies.
Photo-immunomodulation for cancer therapy
Exploiting the highly immunogenic cell death produced by reactive oxygen species that occur in photodynamic therapy, we designed a series of peptide-drug conjugates where the drug is an FDA approved photosensitizer used in photodynamic therapy. These conjugates display higher in vitro toxicity than chemotherapeutic agents, to cells expressing the peptide receptors, and are activated by light. We are currently working on a multipronged therapy that acts on cancer cells, cancer associated fibroblasts (CAFs), and tumor-associated macrophages.
Figure 2. Orally administered “TrimUNO” peptide (shown in green) targets pro-tumoral macrophages (shown in red) of orthotopic triple negative breast tumors in mice, as evidenced by the green-red colocalization (yellow).
Targeting Glioblastoma and Alzheimer’s Disease (AD)
By performing in vivo phage display we have identified a peptide designated as “CES” that homes to intracranial glioblastoma and brains of mice with Alzheimer´s Disease, when administered intravenously (Figure 3). We are now working on a CES-photosensitizer conjugate for photo-immunotherapy.
Figure 3: Intravenously administered “CES” peptide (shown in green) targets intracranial glioblastoma (left panel) and the brain vasculature in Alzheimer´s disease (right panel).
In the past, using in vivo phage display in mouse models of brain injury and AD, we identified peptides that recognize chondroitin sulfate proteoglycans in the brain injury and Connective Tissue Growth Factor (CTGF) in early and late AD, respectively (Mann & Scodeller, Nat. Comm 2016, Nat. Comm. 2017). We are interested in utilizing AD targeting peptides to deliver imaging contrast agents for early detection of AD.
Identification of new targeting peptides
Unbiased screens are used to identify peptide binders to a disease of interest by using mouse models of the disease, the synthetic peptide is later validated, and its receptor is determined using affinity chromatography. This step might reveal a novel biomarker of the disease, as was the case when we identified the receptor of the “DAG” peptide as being a biomarker of early AD (Mann & Scodeller, Nat. Comm. 2017). Alternatively, cell-free screens are performed on immobilized recombinant known markers of interest. The peptide libraries are normally of the type CX7C (C: cysteine, X: random amino acid) and are displayed at the C-terminus of a coat protein of the T7 bacteriophage virus. For this research line we collaborate closely with the lab of Prof. Tambet Teesalu at the University of Tartu, Estonia. The identified peptides may be subject to chemical modifications, to improve their affinity, oral availability, or stability; or coupled to polymeric systems to obtain avidity and an increase in half-life.
Laboratory Members
