#5420 A MODULAR INTRACELLULAR HIERARCHICAL-RESPONSIVE NANOCARRIER ENABLES DUAL TARGETING FOR HIGH THERAPEUTIC EFFICACY IN KIDNEY DISEASE

Abstract

Abstract Background and Aims Single-loaded nanocarrier that can improve targeting capability and drug toxicity compared with free drugs demonstrates a promising strategy for disease treatment. Due to the heterogeneity of the injured cells during the disease progression, dose-induced drug resistance, and instability of nanocarriers in the blood circulation, it is challenging to achieve dual targeting to different injured cell subsets as well as reducing drug dosage but obtaining efficient treatment. In addition, developing nanocarriers is a complex and time-consuming process; there is a desire to develop a universal nanocarrier for various diseases, especially complex ones. Here, we have successfully designed a modular nanocarrier capable of co-delivery drugs. Meanwhile, the effective dosage was reduced to one-tenth of single-loaded nanocarriers. Method The dual-loaded drug-targeting nanoparticles consist of four main modules, including a chemical material, an antibody, and two drugs. First, we constructed a mesoscale spherical nanoparticle with a particle size of 400 nm from PLGA and wrapped drug A inside it. Next, the foot cell-specific antibody Nephrin is used as the target material and modified on the nanoparticle surface by the ph-sensitive short peptide. Finally, drug B is coupled to the antibody to obtain the final dual-targeting dual-drug nanoparticles. The dual-targeting dual-drug nanoparticles were injected into mice via the tail vein to evaluate their toxicity to organs and the immune system and compared with free drug. We explored the targeting and mechanisms of dual-targeting nanoparticles by organ imaging, Immunofluorescence, and other experimental methods. In mice, we established the model of acute kidney injury, puromycin aminonucleoside nephropathy (PAN), and ccRCC to compare the protective effects and mechanisms of dual targeting nanoparticles in different concentrations. Results Dual targeting nanoparticles loaded with different drugs demonstrated the ability of dual targeting of glomeruli and tubules. In treating acute kidney injury, the nanocarriers were encapsulated with rapamycin and dexamethasone acetate; for puromycin nephropathy, the drugs were changed to rapamycin and captopril; and in the treatment of kidney cancer models, gefitinib and glutathione were chosen as targeted antitumor drugs. For different diseases, the lesions were treated significantly with different drug combinations. We observed a reduction of tubular injury in the acute kidney injury model, a recovery of the foot process of podocytes in the puromycin nephropathy model, and a reduction of cancer foci in the renal cancer model. These results show that dual drug-loaded nanomaterials have an excellent ability to cope with complex situations. Conclusion Dual drug delivery system can flexibly adapt the treatment of various diseases by changing particle size, surface antibodies, and drugs.