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Review
. 2024 May 10;25(10):5213.
doi: 10.3390/ijms25105213.

Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics

Jesús David Urbano-Gámez  1   2 , Cinzia Guzzi  1   2 , Manuel Bernal  2   3 , Juan Solivera  4 , Iñigo Martínez-Zubiaurre  5 , Carlos Caro  1   2 , María Luisa García-Martín  1   2   6
Affiliations
Review

Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics

Jesús David Urbano-Gámez et al. Int J Mol Sci. .

Abstract

The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of "tumor targeting" and "tumor cell targeting" are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where 'smart design' refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.

Keywords: biological barriers; cancer; metallic nanoparticles; theranostics; tumor cell targeting in vivo; tumor targeting in vivo.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Systemic clearance of nanoparticles. Following intravenous injection, nanoparticles are distributed systemically through the bloodstream. They reach the liver and the spleen, where tissue-resident macrophages (called Kupffer cells in the liver) and endothelial cells (LSEC) sequester a large portion of the administered dose. Nanoparticles small enough to pass the glomerular filter (below ~5 nm) are excreted in the urine. The remaining nanoparticles have the opportunity to accumulate in tumor tissues [53]. Adapted. Copyright (2019) Frontiers.
Figure 2
Figure 2
Physiological characteristics of tumor tissue and vasculatures that can facilitate or prevent cancer drug delivery [71]. Adapted. Copyright (2014) Ivyspring.
Figure 3
Figure 3
(a) Magnetic tumor targeting as a proof-of-concept experiment. (b) Representative T2-weighted MR images (top) and parametric T2 maps (bottom) at 0 and 1 h after NP injection. Thick arrows indicate the main zones of magnetically-guided accumulation of the NPs (tumor periphery). (c) ΔR2 (s−1) at the whole tumor or tumor periphery at 1 h post-intravenous administration of the NPs, calculated from the quantitative T2 map analysis. Differences were considered statistically significant at p < 0.01 (*), compared to 0 h. PB staining of histological sections of the tumors, 1 h after NP administration, and with (d) and without (e) magnetic targeting. Bar lengths: 100 μm. Representative T1-weighted MR image (f) and short-term MRI characterization of the distribution of Gadovist® in the whole tumor (g) and tumor periphery (h), drawn with orange lines, after its intravenous administration. The blue lines in g and h refer exclusively to the tumors where the NPs were targeted magnetically before. Differences in the values (%) could be attributed to minor vascularization differences in the area selected manually, which could contain a necrotic zone where Gadovist® may show a slower enhancement curve [93]. Adapted. Copyright (2023) Elsevier.
Figure 4
Figure 4
Design of nanoparticles for active uptake (created with BioRender.com). (A) Monoclonal antibodies, (B) fabs, (C) small peptides, (D) natural proteins, (E) aptamers, (F) carbohydrates, and (G) small molecules [124]. Adapted. Copyright (2020) Frontiers.
Figure 5
Figure 5
Scheme representing tumor targeting (either passive or active) versus tumor cell targeting.
See this image and copyright information in PMC

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Grants and funding

C. Caro thanks the Regional Ministry of Health and Families for his senior postdoctoral grant (RH-0040-2021). Financial support was provided by the Spanish Ministry of Science and Innovation (PID2020-118448RB-C21) (funded by MCIN/AEI/10.13039/50110001103) and the Regional Ministry of Economic Transformation, Industry, Knowledge, and Universities of Andalusia (PAIDI 2020. P20_00727). Financial support was also provided through the contract granted to J.D. Urbano-Gámez, funded by the European Union-NextGenerationEU, and the Plan de Recuperación, Transformación y Resiliencia, through grant number MA/INV/0008/2022 by the Consejería de Empleo, Formación y Trabajo Autónomo of the Junta de Andalucía in the 2022 call of the Programa Investigo, Mecanismo de Recuperación y Resiliencia. M. Bernal was supported by Juan de la Cierva—Incorporation Program (IJC2018-037657-I), Spanish Ministry of Science and Innovation, and currently, he is supported by A.4. Fellowship (“Ayudas para la Incorporación de Doctores”), II Plan Propio (University of Malaga).

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