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Article

Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model

by
Nádia Ribeiro
1,†,
Melissa Albino
2,†,
Andreia Ferreira
3,
Cristina Escrevente
3,
Duarte C. Barral
3,
João Costa Pessoa
1,
Catarina Pinto Reis
2,4,
Maria Manuela Gaspar
2,*,‡ and
Isabel Correia
1,*,‡
1
Centro Química Estrutural, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
2
Research Institute for Medicines (iMed.Ulisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
3
iNOVA4Health, NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal
4
IBEB, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(12), 6728; https://doi.org/10.3390/ijms23126728
Submission received: 25 May 2022 / Revised: 7 June 2022 / Accepted: 14 June 2022 / Published: 16 June 2022
(This article belongs to the Special Issue Development of Responsive Nanoparticles for Cancer Therapy 2.0)

Abstract

Colorectal cancer is the second leading cause of cancer-related mortality. Many current therapies rely on chemotherapeutic agents with poor specificity for tumor cells. The clinical success of cisplatin has prompted the research and design of a huge number of metal-based complexes as potential chemotherapeutic agents. In this study, two zinc(II) complexes, [ZnL2] and [ZnL(AcO)], where AcO is acetate and L is an organic compound combining 8-hydroxyquinoline and a benzothiazole moiety, were developed and characterized. Analytical and spectroscopic studies, namely, NMR, FTIR, and UV-Vis allowed us to establish the complexes’ structures, demonstrating the ligand-binding versatility: tetradentate in [ZnL(AcO)] and bidentate in [ZnL2]. Complexes were screened in vitro using murine and human colon cancer cells cultured in 2D and 3D settings. In 2D cells, the IC50 values were <22 µM, while in 3D settings, much higher concentrations were required. [ZnL(AcO)] displayed more suitable antiproliferative properties than [ZnL2] and was chosen for further studies. Moreover, based on the weak selectivity of the zinc-based complex towards cancer cell lines in comparison to the non-tumorigenic cell line, its incorporation in long-blood-circulating liposomes was performed, aiming to improve its targetability. The resultant optimized liposomal nanoformulation presented an I.E. of 76% with a mean size under 130 nm and a neutral surface charge and released the metal complex in a pH-dependent manner. The antiproliferative properties of [ZnL(AcO)] were maintained after liposomal incorporation. Preliminary safety assays were carried out through hemolytic activity that never surpassed 2% for the free and liposomal forms of [ZnL(AcO)]. Finally, in a syngeneic murine colon cancer mouse model, while free [ZnL(AcO)] was not able to impair tumor progression, the respective liposomal nanoformulation was able to reduce the relative tumor volume in the same manner as the positive control 5-fluorouracil but, most importantly, using a dosage that was 3-fold lower. Overall, our results show that liposomes were able to solve the solubility issues of the new metal-based complex and target it to tumor sites.
Keywords: zinc complexes; hydrazone; liposomes; colorectal cancer; 2D and 3D cell models; in vivo studies zinc complexes; hydrazone; liposomes; colorectal cancer; 2D and 3D cell models; in vivo studies

Share and Cite

MDPI and ACS Style

Ribeiro, N.; Albino, M.; Ferreira, A.; Escrevente, C.; Barral, D.C.; Pessoa, J.C.; Reis, C.P.; Gaspar, M.M.; Correia, I. Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model. Int. J. Mol. Sci. 2022, 23, 6728. https://doi.org/10.3390/ijms23126728

AMA Style

Ribeiro N, Albino M, Ferreira A, Escrevente C, Barral DC, Pessoa JC, Reis CP, Gaspar MM, Correia I. Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model. International Journal of Molecular Sciences. 2022; 23(12):6728. https://doi.org/10.3390/ijms23126728

Chicago/Turabian Style

Ribeiro, Nádia, Melissa Albino, Andreia Ferreira, Cristina Escrevente, Duarte C. Barral, João Costa Pessoa, Catarina Pinto Reis, Maria Manuela Gaspar, and Isabel Correia. 2022. "Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model" International Journal of Molecular Sciences 23, no. 12: 6728. https://doi.org/10.3390/ijms23126728

APA Style

Ribeiro, N., Albino, M., Ferreira, A., Escrevente, C., Barral, D. C., Pessoa, J. C., Reis, C. P., Gaspar, M. M., & Correia, I. (2022). Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model. International Journal of Molecular Sciences, 23(12), 6728. https://doi.org/10.3390/ijms23126728

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