Synergistic Efficacy of Dual-Target HSA-Based Delivery for HER and VEGFR Co-Blockade in Triple-Negative Breast Cancer

Rostaminasab, Sadegh; Memarkashani, Sahar; rahdari, tahereh; Asghari, Seyed Mohsen

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Rostaminasab S, Memarkashani S, rahdari T, Asghari S M. Synergistic Efficacy of Dual-Target HSA-Based Delivery for HER and VEGFR Co-Blockade in Triple-Negative Breast Cancer. Int J Mol Cell Med 2025;
URL: http://ijmcmed.org/article-1-2652-en.html

Synergistic Efficacy of Dual-Target HSA-Based Delivery for HER and VEGFR Co-Blockade in Triple-Negative Breast Cancer

Sadegh Rostaminasab¹

, Sahar Memarkashani¹

, Tahereh Rahdari²

, Seyed Mohsen Asghari³

1- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
2- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
3- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. , sm.asghari@ut.ac.ir

Abstract: (33 Views)

Resistance to monotherapies targeting receptor tyrosine kinases remains a major challenge in triple‑negative breast cancer (TNBC). Here, we developed a dual‑target HSA‑based nanobioconjugate combining human serum albumin (HSA)‑encapsulated Lapatinib—an EGFR1/2 inhibitor—with the VEGFR1/2‑blocking peptide VGB3 to achieve coordinated HER and VEGFR inhibition. Molecular docking predicted stable hydrogen‑bond and hydrophobic interactions between Lapatinib (free and HSA‑bound) and EGFR1/2, and between VGB3 and VEGFR1/2. HSA encapsulation enabled pH‑responsive, sustained drug release with faster kinetics under mildly acidic tumor conditions. Thermal denaturation assays confirmed increased conformational stability of HSA after binding, indicating structural integrity and biocompatibility. In vitro studies revealed that HSA‑Lapatinib exhibited a ~55 % reduction in IC₅₀ (from ≈ 71 µM to ≈ 32 µM) compared with free Lapatinib. The combination of 17 µM HSA‑Lapatinib and 0.18 µM VGB3 reduced cell viability to 25 % (CI = 0.29), confirming a strong synergistic effect. Flow‑cytometric analysis demonstrated a significant increase in apoptosis—from 40.8 % (HSA–Lapatinib) to 46.8 % (combination) (P < 0.05). RT‑PCR further showed a fourfold upregulation of VEGFR2 (P < 0.0001), supporting that HSA‑Lapatinib triggers compensatory VEGFR2 activation which is neutralized by VGB3. Collectively, these findings substantiate a mechanistic and quantitative synergy between HSA‑mediated HER inhibition and VGB3‑based VEGFR blockade. This dual‑target HSA‑Lapatinib/VGB3 system offers enhanced potency, reduced resistance, and a promising platform for precision‑guided TNBC therapy.

Keywords: Triple-negative breast cancer, human serum albumin, Lapatinib, VEGFR2 upregulation, VGB3 peptide, Dual target therapy.

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Type of Study: Original Article | Subject: Medical Pharmacology
Received: 2025/09/1 | Accepted: 2025/12/7 | Published: 2025/07/28