A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

Falgàs, Aïda; Pallarès, Víctor; Unzueta, Ugutz; Céspedes, María Virtudes; Arroyo‐Solera, Irene; Moreno, Marı́a José; Sierra, Jorge; Gallardo, Alberto; Mangues, María Antònia; Vázquez, Esther; Villaverde, Antonio; Mangues, Ramón; Casanova, Isolda

doi:10.3324/haematol.2018.211490

Cited by 46 publications

(47 citation statements)

References 41 publications

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“…This possibility is fully supported by the easy detection within the 0-48 h period, using the same FLI and WB techniques, of the full-length protein in blood, and full-length and proteolyzed protein in tumor tissue (but not in liver or kidney, except at 10 min). [20] Taken together, all these observations, including those involving the control T22-GFP-H6 material in vitro and in vivo, supported the specificity of the treatment and the successful targeting of a highly cytotoxic protein, in the form of proteinonly nanoparticles, from a remote implantation site. The data also validated T22-PE24-H6 as a structurally robust anti-metastatic agent that in an oligomeric form, performed in an excellent way, in the form of stable CXCR4-targeted nanoparticles and in the absence of proteolytic degradation and toxin leakage during the circulation and permanence in the blood stream.…”

mentioning

confidence: 67%

“…Approximately 0.5 mL of blood was obtained in EDTA‐anticoagulated tubes, to measure the exact volume of plasma and the emitted fluorescence at each time point. In addition, samples were cryopreserved in liquid nitrogen for protein extraction and to measure the amount of T22‐GFP‐H6 protein by WB at the injection point, tumor, liver, and kidney as previously described …”

Section: Methodsmentioning

confidence: 99%

“…In addition, samples were cryopreserved in liquid nitrogen for protein extraction and to measure the amount of T22-GFP-H6 protein by WB at the injection point, tumor, liver, and kidney as previously described. [20] Evaluation of Antitumoral and Antimetastatic Activity: To evaluate the effect of IBs material, human tumor xenograft models were used. These in vivo models have a high degree of correlation between sensitivity of disease-specific human xenografts and complete clinical response rates implantation.…”

Section: Methodsmentioning

confidence: 99%

“…These data might indicate a low sensitivity for FLI or WB for the detection of soluble nanoparticle released from the IBs (its sustained release might maintain nanoparticle concentration low in blood, despite being extended in time). This possibility is fully supported by the easy detection within the 0–48 h period, using the same FLI and WB techniques, of the full‐length protein in blood, and full‐length and proteolyzed protein in tumor tissue (but not in liver or kidney, except at 10 min) …”

Section: Reduction Of Metastatic Foci Induced By Pe24 Ibs Treatmentmentioning

confidence: 98%

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Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci

et al. 2019

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Functional amyloids produced in bacteria as nanoscale inclusion bodies are intriguing but poorly explored protein materials with wide therapeutic potential. Since they release functional polypeptides under physiological conditions, these materials can be potentially tailored as mimetic of secretory granules for slow systemic delivery of smart protein drugs. To explore this possibility, bacterial inclusion bodies formed by a self‐assembled, tumor‐targeted Pseudomonas exotoxin (PE24) are administered subcutaneously in mouse models of human metastatic colorectal cancer, for sustained secretion of tumor‐targeted therapeutic nanoparticles. These proteins are functionalized with a peptidic ligand of CXCR4, a chemokine receptor overexpressed in metastatic cancer stem cells that confers high selective cytotoxicity in vitro and in vivo. In the mouse models of human colorectal cancer, time‐deferred anticancer activity is detected after the subcutaneous deposition of 500 µg of PE24‐based amyloids, which promotes a dramatic arrest of tumor growth in the absence of side toxicity. In addition, long‐term prevention of lymphatic, hematogenous, and peritoneal metastases is achieved. These results reveal the biomedical potential and versatility of bacterial inclusion bodies as novel tunable secretory materials usable in delivery, and they also instruct how therapeutic proteins, even with high functional and structural complexity, can be packaged in this convenient format.

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mentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Reduction Of Metastatic Foci Induced By Pe24 Ibs Treatmentmentioning

confidence: 98%

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Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci

et al. 2019

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“…To detect cell surface expression of CXCR4 in AML cell lines, fluorescence-activated cell sorting (FACS) analysis was performed as described before [26]. Two technical and three biological replicates were performed.…”

Section: Quantitation Of Cxcr4 Membrane Levels In Aml Cell Linesmentioning

confidence: 99%

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

et al. 2020

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Background: Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods:Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups.Results: T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model.(Continued on next page)

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In Vitro Fabrication of Microscale Secretory Granules

López‐Laguna

Parladé

Álamo

et al. 2021

Adv Funct Materials

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Advanced medical treatments involving drug delivery require fully biocompatible materials with the ability to release functional drugs in a time-prolonged way. Ideally, the delivered molecules should be self-contained as chemically homogenous entities to prevent the use of potentially toxic scaffolds or hold matrices. In nature, peptidic hormones are self-stored in protein-only secretory granules formed by the reversible coordination of Zn 2+ and histidine residues. Inspired by this concept, an in vitro transversal procedure is developed, analyzed, and comparatively applied for the fabrication of protein-only secretory granules at the microscale. These materials can be produced from any polyhistidine-tagged protein using physiological concentrations of Zn 2+ as a potent and versatile glue-like agent. The screening of granules formed by 12 engineered and nonengineered proteins at different Zn 2+ concentrations revealed optimal fabrication conditions and the consequent release profiles. Moreover, the functional and structural properties of the delivered protein are fully validated using a drug-targeting protein platform in a mouse model of human colorectal cancer. In summary, short histidine tags allow the packaging of structurally and functionally dissimilar polypeptides, which supports the proposed fabrication method as a powerful protocol extensible to diverse clinical scenarios in which slow protein drug delivery is required.

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A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

Cited by 46 publications

References 41 publications

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

In Vitro Fabrication of Microscale Secretory Granules

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