Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

Voltà‐Durán, Eric; Serna, Naroa; Sánchez‐García, Laura; Aviñó, Anna; Sánchez, Julieta M.; López‐Laguna, Hèctor; Cano‐Garrido, Olivia; Casanova, Isolda; Mangues, Ramón; Eritja, Ramón; Vázquez, Esther; Villaverde, Antonio; Unzueta, Ugutz

doi:10.1016/j.actbio.2020.11.018

Cited by 18 publications

(17 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, it must be noted that T22, in form of different types of protein-only nanoparticles (including GFP, BFP or iRFP) has been never observed as inducer of cell toxicity or apoptosis in cell culture or in vivo, in different animal models of human cancers [16,[46][47][48][49][50][51]. However, the use of T22-based vehicles to deliver small cytotoxic drugs [17,52,53] or proteins [24,40,45,48,54] result in highly selective tumor tissue destruction. These consistent observations confirm that in the biparatopic materials EPI-X4 is associated to cell toxicity while T22 to enhanced targeting.…”

Section: Discussionmentioning

confidence: 99%

Biparatopic Protein Nanoparticles for the Precision Therapy of CXCR4+ Cancers

Cano‐Garrido

Álamo

Sánchez‐García

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

The accumulated molecular knowledge about human cancer enables the identification of multiple cell surface markers as highly specific therapeutic targets. A proper tumor targeting could significantly avoid drug exposure of healthy cells, minimizing side effects, but it is also expected to increase the therapeutic index. Specifically, colorectal cancer has a particularly poor prognosis in late stages, being drug targeting an appropriate strategy to substantially improve the therapeutic efficacy. In this study, we have explored the potential of the human albumin-derived peptide, EPI-X4, as a suitable ligand to target colorectal cancer via the cell surface protein CXCR4, a chemokine receptor overexpressed in cancer stem cells. To explore the potential use of this ligand, self-assembling protein nanoparticles have been generated displaying an engineered EPI-X4 version, which conferred a modest CXCR4 targeting and fast and high level of cell apoptosis in tumor CXCR4+ cells, in vitro and in vivo. In addition, when EPI-X4-based building blocks are combined with biologically inert polypeptides containing the CXCR4 ligand T22, the resulting biparatopic nanoparticles show a dramatically improved biodistribution in mouse models of CXCR4+ human cancer, faster cell internalization and enhanced target cell death when compared to the version based on a single ligand. The generation of biparatopic materials opens exciting possibilities in oncotherapies based on high precision drug delivery based on the receptor CXCR4.

show abstract

Section: Discussionmentioning

confidence: 99%

Biparatopic Protein Nanoparticles for the Precision Therapy of CXCR4+ Cancers

Cano‐Garrido

Álamo

Sánchez‐García

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…While nanocarriers improve the drug biodistribution and passive and active targeting, reduce renal clearance, protect the drug from degradation, and enhance cell uptake, only a fraction of the administered drug reaches the tumor tissue. Further, the persistence of the carrier in the tumor and healthy tissues leads to undesired toxic effects [ 94 , 95 ]. NPs based on multifunctional proteins that are degraded by natural enzymatic pathways are attractive as a carrier for passive or active drug targeting to tumors [ 96 ].…”

Section: Self-assembling Protein Npsmentioning

confidence: 99%

“…The T22 peptide facilitated the binding and internalization of the NPs in CXCR4 + tumor cells for targeted intracellular drug delivery. In a recent study, the drugs, oligo-floxuridine (FdU) and monomethyl auristatine E (MMAE), were chemically coupled to exotoxin A from Pseudomonase aeruginosa and diphtheria toxin from Corynebacterium diphtheria, respectively, to form self-assembled protein NPs with an average size of 50 nm targeting CXCR4 + tumor cells [ 95 ]. Based on in vitro studies, the resulting protein NPs were internalized by CXCR4 + cells and inhibited the growth of tumor cells.…”

Section: Self-assembling Protein Npsmentioning

confidence: 99%

Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells: A Review of Recent Advances

et al. 2021

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are a subpopulation of cells that can initiate, self-renew, and sustain tumor growth. CSCs are responsible for tumor metastasis, recurrence, and drug resistance in cancer therapy. CSCs reside within a niche maintained by multiple unique factors in the microenvironment. These factors include hypoxia, excessive levels of angiogenesis, a change of mitochondrial activity from aerobic aspiration to aerobic glycolysis, an upregulated expression of CSC biomarkers and stem cell signaling, and an elevated synthesis of the cytochromes P450 family of enzymes responsible for drug clearance. Antibodies and ligands targeting the unique factors that maintain the niche are utilized for the delivery of anticancer therapeutics to CSCs. In this regard, nanomaterials, specifically nanoparticles (NPs), are extremely useful as carriers for the delivery of anticancer agents to CSCs. This review covers the biology of CSCs and advances in the design and synthesis of NPs as a carrier in targeting cancer drugs to the CSC subpopulation of cancer cells. This review includes the development of synthetic and natural polymeric NPs, lipid NPs, inorganic NPs, self-assembling protein NPs, antibody-drug conjugates, and extracellular nanovesicles for CSC targeting.

show abstract

“…Although several structural variants of polyphemusin peptides have been tested for antimicrobial properties [24,25], T22 has been never explored in this regard. Considering the growing need for new antimicrobial agents and the proved clinical potential of T22 in cell-targeted drug delivery [11,18,29], the detection of any new antimicrobial activities in this peptide would be of broad interest and deserves a thorough investigation. More so, these functionalities might be conserved in T22 peptides displayed on multimeric protein nanoparticles, since antimicrobial activities largely benefit from nanostructured and multivalent presentations [30,31].…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

et al. 2021

Self Cite

View full text Add to dashboard Cite

CXCR4 is a cytokine receptor used by HIV during cell attachment and infection. Overexpressed in the cancer stem cells of more than 20 human neoplasias, CXCR4 is a convenient antitumoral drug target. T22 is a polyphemusin-derived peptide and an effective CXCR4 ligand. Its highly selective CXCR4 binding can be exploited as an agent for the cell-targeted delivery and internalization of associated antitumor drugs. Sharing chemical and structural traits with antimicrobial peptides (AMPs), the capability of T22 as an antibacterial agent remains unexplored. Here, we have detected T22-associated antimicrobial activity and biofilm formation inhibition over Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, in a spectrum broader than the reference AMP GWH1. In contrast to GWH1, T22 shows neither cytotoxicity over mammalian cells nor hemolytic activity and is active when displayed on protein-only nanoparticles through genetic fusion. Under the pushing need for novel antimicrobial agents, the discovery of T22 as an AMP is particularly appealing, not only as its mere addition to the expanding catalogue of antibacterial drugs. The recognized clinical uses of T22 might allow its combined and multivalent application in complex clinical conditions, such as colorectal cancer, that might benefit from the synchronous destruction of cancer stem cells and local bacterial biofilms.

show abstract

Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

Cited by 18 publications

References 96 publications

Biparatopic Protein Nanoparticles for the Precision Therapy of CXCR4+ Cancers

Biparatopic Protein Nanoparticles for the Precision Therapy of CXCR4+ Cancers

Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells: A Review of Recent Advances

Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

Contact Info

Product

Resources

About