Preparation and characterization of PE38KDEL-loaded anti-HER2 nanoparticles for targeted cancer therapy
Abstract
The clinical use of immunotoxins is severely limited by nonspecific toxicity. To overcome this limitation, PE38KDEL was used as a model protein toxin to prepare PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) antibody modified nanoparticles (NPs), which were covalently conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2) by a two-step carbodiimide method. The characterization of the PE38KDEL-loaded nanoparticles-anti-Fab' bioconjugates (PE-NPs-HER), such as particle size, zeta potential and morphology, were evaluated by dynamic light-scattering detector and transmission electron microscope (TEM). Micro BCA assay was used to determine the drug encapsulation efficiency and the quantity of Fab' conjugated with NPs. The binding affinity and internalization efficiency of PE-NPs-HER were demonstrated by flow cytometry and laser-scanning confocal microscopy. In comparison with PE38KDEL-loaded nanoparticles (PE-NPs) that lack anti-HER2 Fab', PE-NPs-HER had superior in vitro cytotoxicity against HER2-overexpressing breast cancer cell lines. Progressively, PE-NPs-HER has superior protective antitumor activity in HER2-overexpressing tumor-bearing mice than the control immunotoxin PE-HER constructed by chemically coupling PE38KDEL to rhuMAbHER2. Most strikingly, in developed HER2-overexpressing tumor xenograft model, administration of PE-NPs-HER (0.9 mg/kg) showed a much better therapeutic efficacy in inhibiting tumor growth compared with PE-HER and other controls: final mean tumor load was 13+/-6 mm(3) (mean+/-SD; n=8, significantly smaller than all other groups by ANOVA at 95% confidence interval). In addition, PE-NPs-HER were well tolerated in mice with a much higher MTD (maximally tolerated dose) than PE-HER (2.92 mg/kg vs. 0.92 mg/kg), indicating the systemic toxicity of PE38KDEL was dramatically reduced by PLGA encapsulation. Thus, the bioconjugates PE-NPs-HER may represent a potentially useful strategy for cancer therapy.
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The use of Fab' fragments helps the antibody-modified NPs to better penetrate into solid tumors.
“The use of Fab’ fragments helps the antibody-modified NPs to better penetrate into solid tumors.”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [201]
The modified nanoparticles have better anti-tumor activity in vivo and in vitro against breast cancer overexpressing HER2.
“The results also show that the modified nanoparticles have better anti-tumor activity in vivo and in vitro against breast cancer overexpressing HER2.201”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [201]
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- Authors
- Chen, H., Gao, J., Lu, Y., Kou, G., Zhang, H., Fan, L., Sun, Z., Guo, Y., & Zhong, Y.
- Affiliations
- Second Military Medical University (CN)
- Corresponding author
- Guo, Yajun
- Zhong, Yanqiang
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 128
- Issue
- 3
- Pages
- 209-216
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2071930394
- Cited by
- 97
- References
- 35
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 3 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Shanghai Jiao Tong University
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- immunotoxins, HER2, anti-HER2 monoclonal antibody, PLGA nanoparticles, antibody-conjugated nanoparticles, Fab fragment, targeted cancer therapy, breast cancer, tumor xenografts, encapsulation efficiency, cytotoxicity, systemic toxicity, tumor growth inhibition
- MeSH terms
- Polylactic Acid-Polyglycolic Acid Copolymer, Pseudomonas aeruginosa Exotoxin A, Animals, Antibodies, Monoclonal, Antibody Specificity, Immunotoxins, Antineoplastic Agents, Bacterial Toxins, Breast Neoplasms, Cell Survival, Dose-Response Relationship, Drug, Drug Carriers, Endocytosis, Exotoxins, Female, Glycolates, Humans, Immunoglobulin Fab Fragments, Mice, Inbred BALB C, Mice, Nude, Particle Size, Polyglycolic Acid, Recombinant Proteins, Surface Properties, Time Factors, Erb-b2 Receptor Tyrosine Kinases, Lactic Acid, Inhibitory Concentration 50, Xenograft Model Antitumor Assays, ADP Ribose Transferases, Virulence Factors, Cell Line, Tumor, Mice, Nanoparticles
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