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Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting
Hong Yeol Yoon1, Min Lee Shin1,2, Man Kyu Shim1,3
1Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Abstract:
Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin αvβ3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.
Insights
This study introduces a novel nanoparticle targeting strategy for heterogeneous tumors. By using metabolic engineering to add azide reporters to tumor cells, nanoparticles conjugated with bicyclononyne (BCN) showed improved and uniform tumor targeting compared to traditional methods.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Traditional nanoparticle targeting in cancer therapy relies on biological ligands, which face limitations due to tumor heterogeneity.
- Active-targeting strategies using ligands like aptamers, antibodies, and peptides struggle with inter- and intra-tumor variations.
Purpose of the Study:
- To develop and evaluate an alternative active-targeting strategy for nanoparticles using metabolic engineering and bioorthogonal click chemistry.
- To improve the tumor-targeting efficiency and uniformity of nanoparticles in heterogeneous cancer models.
Main Methods:
- Metabolic engineering was employed to introduce azide-containing chemical reporters onto the surface glycans of various cancer cell lines (lung, brain, breast).
- Bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) were synthesized and compared with cyclic RGD-conjugated CNPs (cRGD-CNPs) for tumor targeting.
- In vitro and in vivo studies assessed nanoparticle accumulation and distribution in tumor tissues and isolated heterogeneous cells.
Main Results:
- Azide reporters were successfully generated on diverse cancer cell lines, including A549, U87, BT-474, MDA-MB231, and MCF-7.
- BCN-CNPs targeting azide reporters demonstrated a 1.6-fold higher fluorescence intensity in tumor tissues compared to cRGD-CNPs.
- Nanoparticle distribution was more uniform in azide-reporter-targeted tumors and heterogeneous U87 cells (∼92.9% binding) compared to cRGD-CNPs.
Conclusions:
- The artificial azide-reporter-targeting strategy, utilizing bioorthogonal click chemistry, effectively targets heterogeneous tumor cells.
- This approach offers a promising alternative to conventional methods for enhancing nanoparticle tumor targeting in cancer therapy.
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