Cetuximab-Modified Human Serum Albumin Nanoparticles Co-Loaded with Doxorubicin and MDR1 siRNA for the Treatment of Drug-Resistant Breast Tumors

Xin Yang; Yifan Wang; Si Chen; Shuang Zhang; Chunying Cui

doi:10.2147/IJN.S332830

Cetuximab-Modified Human Serum Albumin Nanoparticles Co-Loaded with Doxorubicin and MDR1 siRNA for the Treatment of Drug-Resistant Breast Tumors

Int J Nanomedicine. 2021 Oct 16:16:7051-7069. doi: 10.2147/IJN.S332830. eCollection 2021.

Authors

Xin Yang^{1

2

3}, Yifan Wang^{1

2

3}, Si Chen^{1

2

3}, Shuang Zhang^{1

2

3}, Chunying Cui^{1

2

3}

Affiliations

¹ School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China.
² Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, 100069, People's Republic of China.
³ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, 100069, People's Republic of China.

Abstract

Background: Breast cancer is the most prevalent cancer among women. Doxorubicin (DOX) is a common chemotherapeutic drug used to treat many different cancers. However, multidrug resistance limits the treatment of breast cancer. MDR1 siRNA (siMDR1) combinatorial therapy has attracted significant attention as a breakthrough therapy for multidrug resistance in tumors. However, naked siRNA is easily degraded by enzymatic hydrolysis requiring an siRNA carrier for its protection. Human serum albumin (HSA) was selected as the carrier due to its excellent biocompatibility, non-toxicity, and non-immunogenicity. Cetuximab was used to modify the HSA nanoparticles in order to target the tumor tissues.

Methods: This study used a central composite design response surface methodology (CCD-RSM) to investigate the optimal formula for HSA NPs preparation. Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy. The efficacy of C-H/D/M tumor growth inhibitory activity was investigated in vitro and in vivo using confocal imaging, MTT assay, and an MCF-7/ADR tumor-bearing mice model. RT-qPCR, ELISA analysis, and flow cytometry were used to investigate the in vitro antitumor mechanisms of C-H/D/M.

Results: The diameter and PDI of the C-H/D/M were 173.57 ± 1.30 nm and 0.027 ± 0.004, respectively. C-H/D/M promoted and maintained the sustained release and the uptake of DOX significantly. After transfection, the MDR1 mRNA and P-gp expression levels were down-regulated by 44.31 ± 3.6% (P < 0.01) and 38.08 ± 2.4% (P < 0.01) in an MCF-7/ADR cell line. The fluorescent images of the treated BALB/c nude mice revealed that C-H/D/M achieved targeted delivery of siMDR1 and DOX into the tumor tissue. The in vivo tumor inhibition results demonstrated that the tumor inhibition rate of the C-H/D/M treated group was 54.05% ± 1.25%. The biosafety results indicated that C-H/D/M did not induce significant damages to the main organs in vivo.

Conclusion: C-H/D/M can be used as an ideal non-viral tumor-targeting vector to overcome MDR and enhance the antitumor effect.

Keywords: HSA; MDR; co-delivery carrier; gene silencing; human serum albumin; multidrug resistance; small interfere RNA.

MeSH terms

Animals
Breast Neoplasms* / drug therapy
Cell Line, Tumor
Cetuximab
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Nanoparticles*
Pharmaceutical Preparations*
RNA, Small Interfering / genetics
Serum Albumin, Human

Substances

Pharmaceutical Preparations
RNA, Small Interfering
Doxorubicin
Cetuximab
Serum Albumin, Human

Grants and funding

This work was supported by the National Natural Science Foundation (81502688), Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KM201810025019), and a basic-clinical key research grant (16JL72, 17JL67) from Capital Medical University, the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (2013–2015).