Multifunctional Nanoassemblies for Cytotoxic Drug and Therapeutic Enzymes Delivery in Neuroblastoma Therapy

Parra‐Nieto, Jorge; Cid, María Amor García del; Galeano, Carolina; Cárcer, I. Aguirre de; García‐García, Lorena; González‐Murillo, África; Megı́as, Diego; Ramı́rez, Manuel; Baeza, Alejandro

doi:10.1002/admi.202201356

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…Third, we proposed the monoclonal antibody Dinutuximab conjugated with FITC as a specific strategy to facilitate NB targeting through recognition by anti-FITC CAR-T cells. However, other approaches based on MABG (an analogue of MIBG) developed before ( 52 – 54 ) could also be used to target NB in combination with FITC and anti-FITC CAR-T cells. Some authors have developed anti-GD2 CAR-T cells with limited efficacy ( 37 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma

García-García,

G. Sánchez,

Ivanova

et al. 2024

Front. Immunol.

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IntroductionThe clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2.MethodsWe compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 versus IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines.ResultsThe IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h.ConclusionCB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

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Section: Discussionmentioning

confidence: 99%

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma

García-García,

G. Sánchez,

Ivanova

et al. 2024

Front. Immunol.

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“…The MSN-NH2 was coated with liposome by bilayer formation method with ultrasonic assistance. [18,19] The MSN-NH2 has been dispersed in deionized water with concentration of 1 mg/mL before it was mixed with liposome solution at 60°C for 30 minutes. The mixture was sonicated in ultrasonic bath at 60 °C for 30 minutes to form homogenous solution and reduce multidispersity of particles.…”

Section: Preparation Of Msn@lipmentioning

confidence: 99%

Development of liposome capped mesoporous silica nanoparticle for anticancer drug delivery

Nguyen,

Truong‐Thi

et al. 2023

Vietnam Journal of Chemistry

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Mesoporous silica nanoparticles (MSNs) have been used as an anticancer drug delivery system with high safety and entrapment capacity thanks to their large internal space for drug accommodation, durable structure, and good biocompatibility. However, the treatment efficiency of the bare MSNs is limited due to its drug leakage and burst release. In this study, a phospholipid bilayer was covered on the MSNs surface (MSN@Lip) as a liposomal cap that not only reduced drug leakage but also improved the stability of the colloidal system. The chemical structure of MSNs and MSN@Lip was characterized by Fourier transform infrared spectroscopy (FT‐IR) and energy‐dispersive X‐ray spectroscopy (EDX). The particle size and morphology were determined by dynamic light scattering (DLS). The results demonstrated that the MSN@Lip was successfully synthesized with the hydrodynamic diameter and zeta potential of 177.13±1.5 nm and ‐57.57±4.00 mV, respectively. The optimal condition was sonication for 30 minutes at 60°C, with the Lip‐MSNs ratio as 3:1 (w/w). The SEM images showed that MSN@Lip has a spherical shape with high monodispersity. Releasing profile of doxorubicin (DOX) indicated that the formation of liposomal cap on MSN successfully reduced DOX burst release. The MSN@Lip is a potential delivery material for clinical translation because of colloidal stability, good drug loading content, and sustainable drug release.

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Challenges of enzyme therapy: Why two players are better than one

Cuoghi,

Caraffi,

Anderlini

et al. 2024

WIREs Nanomed Nanobiotechnol

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Enzyme‐based therapy has garnered significant attention for its current applications in various diseases. Despite the notable advantages associated with the use of enzymes as therapeutic agents, that could have high selectivity, affinity, and specificity for the target, their application faces challenges linked to physico‐chemical and pharmacological properties. These limitations can be addressed through the encapsulation of enzymes in nanoplatforms as a comprehensive solution to mitigate their degradation, loss of activity, off‐target accumulation, and immunogenicity, thus enhancing bioavailability, therapeutic efficacy, and circulation time, thereby reducing the number of administrations, and ameliorating patient compliance. The exploration of novel nanomedicine‐based enzyme therapeutics for the treatment of challenging diseases stands as a paramount goal in the contemporary scientific landscape, but even then it is often not enough. Combining an enzyme with another therapeutic (e.g., a small molecule, another enzyme or protein, a monoclonal antibody, or a nucleic acid) within a single nanocarrier provides innovative multidrug‐integrated therapy and ensures that both the actives arrive at the target site and exert their therapeutic effect, leading to synergistic action and superior therapeutic efficacy. Moreover, this strategic approach could be extended to gene therapy, a field that nowadays has gained increasing attention, as enzymes acting at genomic level and nucleic acids may be combined for synergistic therapy. This multicomponent therapeutic approach opens opportunities for promising future developments.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies

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Multifunctional Nanoassemblies for Cytotoxic Drug and Therapeutic Enzymes Delivery in Neuroblastoma Therapy

Cited by 5 publications

References 38 publications

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma

Development of liposome capped mesoporous silica nanoparticle for anticancer drug delivery

Challenges of enzyme therapy: Why two players are better than one

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