Protein-driven nanomedicines in oncotherapy

Casanova, Isolda; Unzueta, Ugutz; Arroyo‐Solera, Irene; Céspedes, María Virtudes; Villaverde, Antonio; Mangues, Ramón; Vázquez, Esther

doi:10.1016/j.coph.2018.12.004

Cited by 21 publications

(20 citation statements)

References 66 publications

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“…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 ]. CXCR4 is a viable target in cancer therapy, because it mediates cancer metastasis by inducing the migration of tumor-associated 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

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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.

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Section: Self-assembling Protein Npsmentioning

confidence: 99%

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

et al. 2021

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“…Protein-based drug delivery offers promises in the design of innovative drug delivery systems, especially when intended for precision medicines that require selective penetration of the therapeutic agent into target cells [1]. Proteins and peptides, over other materials commonly explored as drug delivery systems, offer high structural and functional versatility easily regulatable by genetic engineering.…”

Section: Introductionmentioning

confidence: 99%

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering

et al. 2019

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Modular protein engineering is suited to recruit complex and multiple functionalities in single-chain polypeptides. Although still unexplored in a systematic way, it is anticipated that the positioning of functional domains would impact and refine these activities, including the ability to organize as supramolecular entities and to generate multifunctional protein materials. To explore this concept, we have repositioned functional segments in the modular protein T22-GFP-H6 and characterized the resulting alternative fusions. In T22-GFP-H6, the combination of T22 and H6 promotes selfassembling as regular nanoparticles and selective binding and internalization of this material in CXCR4-overexpressing tumor cells, making them appealing as vehicles for selective drug delivery. The results show that the pleiotropic activities are dramatically affected in module-swapped constructs, proving the need of a carboxy terminal positioning of H6 for protein self-assembling, and the accommodation of T22 at the amino terminus as a requisite for CXCR4 + cell binding and internalization. Furthermore, the failure of self-assembling as regular oligomers reduces cellular penetrability of the fusions while keeping the specificity of the T22-CXCR4 interaction. All these data instruct how multifunctional nanoscale protein carriers can be designed for smart, protein-driven drug delivery, not only for the treatment of CXCR4 + human neoplasias, but also for the development of anti-HIV drugs and other pathologies in which CXCR4 is a relevant homing marker.

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“…The combination of both functions is very attractive when designing recombinant protein materials intended for endosomal delivery. Importantly, the application of toxin-based nanoparticles, immunotoxins or generically, protein-based drug vehicles [33,34], would largely benefit from potent endosomolytic agents. This is because lysosomal degradation is a critical bottleneck in the delivery route [35], and in this context, many strategies and active materials are currently developed to enhance the necessary cytosolic delivery [36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

“…This is because lysosomal degradation is a critical bottleneck in the delivery route [35], and in this context, many strategies and active materials are currently developed to enhance the necessary cytosolic delivery [36][37][38][39][40]. On the other side, proteins are becoming increasingly valuable biopharmaceuticals [34,[41][42][43], and H6-based functionalization by gene fusion is a common procedure [44]. However, the use of H6 in clinics might be a source of regulatory concerns, since this peptide might be potentially immunogenic in humans [45][46][47], what pushes to identify alternatives regarding both the nanoarchitectonic and endosomolytic properties of H6.…”

Section: Introductionmentioning

confidence: 99%

Endosomal escape of protein nanoparticles engineered through humanized histidine-rich peptides

et al. 2019

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Poly-histidine peptides such as H6 (HHHHHH) are used in protein biotechnologies as purification tags, protein-assembling agents and endosomal-escape entities. The pleiotropic properties of such peptides make them appealing to design protein-based smart materials or nanoparticles for imaging or drug delivery to be produced in form of recombinant proteins. However, the clinical applicability of H6tagged proteins is restricted by the potential immunogenicity of these segments. In this study, we have explored several humanized histidine-rich peptides in tumor-targeted modular proteins, which can specifically bind and be internalized by the target cells through the tumoral marker CXCR4. We were particularly interested in exploring how protein purification, self-assembling and endosomal escape perform in proteins containing the variant histidine-rich tags. Among the tested candidates, the peptide H5E (HEHEHEHEH) is promising as a good promoter of endosomal escape of the associated fulllength protein upon endosomal internalization. The numerical modelling of cell penetration and endosomal escape of the tested proteins has revealed a negative relationship between the amount of protein internalized into target cells and the efficiency of cytoplasmic release. This fact demonstrates that the His-mediated, proton sponge-based endosomal escape saturates at moderate amounts of internalized protein, a fact that might be critical for the design of protein materials for cytosolic molecular delivery.

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Protein-driven nanomedicines in oncotherapy

Cited by 21 publications

References 66 publications

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

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

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering

Endosomal escape of protein nanoparticles engineered through humanized histidine-rich peptides

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