https://orcid.org/0000-0002-0242-5059
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Abstract
Purpose
The lack of specificity of conventional chemotherapy is one of the main difficulties to be solved in cancer therapy. Biomimetic magnetoliposomes are successful chemotherapy controlled-release systems, hyperthermia, and active targeting agents by functionalization of their surface with monoclonal antibodies. The membrane receptor Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) stands out as colorectal cancer (CRC) biomarker and appears to be related to treatment resistance and the development of metastasis. The aim of this study was to assess the effectiveness and safety of LGR5-targeted biomimetic magnetoliposomes loaded with oxaliplatin (OXA) or 5-fluorouracil (5-FU) in the selective treatment of CRC and their possible application in hyperthermia.
Methods
Synthesis, characterization and determination of heating capacity of magnetoliposomes transporting OXA or 5-FU (with and without LGR5 functionalization) were conducted. In vitro antitumoral activity was assayed in multiple colorectal cell lines at different times of exposition. In addition to this, cell internalization was studied by Prussian Blue staining, flow cytometry and fluorescence microscopy. In vivo acute toxicity of magnetoliposomes was performed to evaluate iron-related toxicity.
Results
OXA and 5-FU loaded magnetoliposomes functionalized with LGR5 antibody showed higher cellular uptake than non-targeted nanoformulation with a reduction of the percentage of proliferation in colon cancer cell lines up to 3.2-fold of the IC50 value compared to that of free drug. The differences between non-targeted and targeted nanoformulations were more evident after short exposure times (4 and 8 hours). Interestingly, assays in the MC38 transduced cells with reduced LGR5 expression (MC38-L(-)), showed lower cell internalization of LGR5-targeted magnetoliposomes compared to non-transduced MC38 cell line. In addition, magnetoliposomes showed an in vitro favorable heating response under magnetic excitation and great iron-related biocompatibility data in vivo.
Conclusion
Drug-loaded magnetoliposomes functionalized with anti-LGR5 antibodies could be a promising CRC treatment strategy for LGR5+ targeted chemotherapy, magnetic hyperthermia, and both in combination.
Graphical Abstract
Ethics Approval
The in vivo experiment was approved by the Research Ethics Committee of Granada University (Reference code: 07/03/2022/023) and in accordance with international standards (European Communities Council Directive 2010/63).
Acknowledgments
A.C and M.J.-C., wants to acknowledge FPU2019 and FPU2021, grants (refs. FPU19/04112, and FPU21/01529) from the Ministerio de Universidades (Spain), and C.L. a P-FIS (PI20-00284) from the Ministerio de Ciencia, Innovación y Universidades (Spain). L.G. wants to acknowledge the Junta de Andalucía 2021 Scholarship (ref. PREDOC_00199) from the “Secretaría General de Universidades, Investigación y Tecnología”, C.J-L. thanks UCE-PP2016-05 and Biotechnology Institute (University of Granada).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Dr Concepcion Jimenez-Lopez reports a patent pending PCT/ES2097070747. The authors declare no other conflicts of interest in this work.