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Abstract: TH-PO759

A Modular Intracellular Hierarchical-Responsive Nanocarrier Enables Dual Targeting for High Therapeutic Efficacy in Kidney Diseases

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Li, Aiqing, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Tao, Zeng, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
Background

Single-drug nanocarriers that can improve targeting capability and reduce drug toxicity compared with free drugs demonstrate a promising strategy for disease treatment. However, due to cell heterogeneity during disease progression, dose-induced drug resistance, and instability of nanocarriers in the blood circulation, achieving dual targeting of different injured cell subsets while reducing drug dosage and maintaining treatment efficacy remains challenging. In addition, developing nanocarriers is a complex and time-consuming process; there is a desire for a universal nanocarrier for various diseases, especially complex diseases. Here, we have successfully designed a modular nanocarrier capable of co-delivering drugs with a reduced effective dosage of one-tenth that of single-drug nanocarriers.</font>

Methods


The dual-drug targeting nanoparticles consist of three main modules: a PLGA nanoparticle, an antibody, and two drugs. We first constructed a 400 nm PLGA nanoparticle encapsulating drug A. Then, the podocyte-specific antibody Nephrin was modified onto the nanoparticle surface. Finally, drug B was coupled to the antibody. The dual-targeting dual-drug nanoparticles were injected into mice to evaluate their toxicity compared with free drugs. We explored the targeting of the nanoparticles using organ imaging and other methods. We established three kidney disease models in mice to compare the effects of dual-targeting nanoparticles at different concentrations.

Results

Dual-targeting nanoparticles loaded with different drugs demonstrated dual targeting of glomeruli and tubules. To treat acute kidney injury, the nanocarriers encapsulated rapamycin and dexamethasone acetate; for PAN, the drugs were rapamycin and captopril; and for the ccRCC model, gefitinib and glutathione were chosen as the targeted antitumor drugs. For different diseases, lesions were significantly treated with different drug combinations. We observed reduced tubular injury in the acute kidney injury model, recovered podocyte foot processes in the PAN model, and reduced cancer foci in the ccRCC model. These results show that dual-drug loaded nanomaterials have an excellent ability to address complex disease presentations.

Conclusion

The dual-drug delivery system can flexibly adapt to treating various diseases by modifying the particle size, surface antibodies, and drugs.

Funding

  • Clinical Revenue Support