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Theranostic vNAR-Based Immunoconjugates Achieve Selective Intracellular Cisplatin Delivery in Embedded 3D
Andrea C Alfonseca-Ladrón de Guevara1, Alejandro Manzanares-Guzmán1, Jessica A Badillo-Mata1
1Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Jalisco, Mexico.
Pharmaceuticals (Basel, Switzerland)
|May 4, 2026
Summary
A novel shark antibody (vNAR R426) delivers cisplatin effectively to HER2-positive breast cancer cells expressing EGFRvIII. This theranostic platform targets cancer heterogeneity and enhances drug delivery for precision medicine.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Precise intracellular delivery of chemotherapeutics is challenging in HER2-positive breast cancer due to intratumoral heterogeneity and limited penetration.
- Epidermal growth factor receptor variant III (EGFRvIII), present in subsets of HER2-positive breast cancers, drives aggressive phenotypes and attenuates therapeutic responses.
- EGFRvIII is a compelling therapeutic target due to its co-expression with HER2 and amplification of oncogenic signaling.
Purpose of the Study:
- To evaluate the shark-derived single-domain antibody vNAR R426 as a modular theranostic platform for receptor-mediated cisplatin delivery.
- To assess the efficacy of vNAR-based immunoconjugates for simultaneous intracellular drug transport and immunofluorescence-based detection in EGFRvIII-positive cells and 3D spheroids.
Main Methods:
- Conjugation of vNAR R426 with cisplatin and fluorescein to create a theranostic platform.
- Evaluation of vNAR-based immunoconjugates in EGFRvIII-positive SKBR3 cells and 3D spheroids.
- Assessment of receptor recognition, internalization, intracellular trafficking, cytotoxicity, and tissue penetration.
Main Results:
- vNAR-CDDP demonstrated potent, receptor-mediated cytotoxicity with an IC50 of 2.68 µM, approximately 50-fold lower than free cisplatin.
- The theranostic vNAR (vNAR_CDDP+FITC) exhibited deep and uniform penetration in 3D spheroid models.
- Cisplatin conjugation did not impair tissue diffusion or receptor engagement, enabling effective payload delivery to both peripheral and central cell populations.
Conclusions:
- vNAR R426 represents a next-generation theranostic platform for addressing intratumoral heterogeneity in HER2-positive breast cancer.
- The modular single-domain scaffold integrates tumor-restricted targeting and efficient intracellular drug delivery.
- This approach combines potent cytotoxic activity with immunofluorescence-based detection, advancing precision therapeutics.
