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

Document Type : Original Article

Authors
Sadegh Rostaminasab 1
Sahar Memarkashani 1
Tahereh Rahdari 2
S. Mohsen Asghari 3
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.
10.22088/IJMCM.BUMS.14.4.1031
Abstract
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-bonding 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 an increase in the
conformational stability of HSA after binding, indicating structural integrity and
biocompatibility. In vitro studies revealed that HSA-Lapatinib exhibited a ~55 %
reduction in IC₅ ₀ (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
VEGFR2upregulation
VGB3 peptide
Dual-target therapy.