Nanostructured Polyvinylpyrrolidone-Curcumin Conjugates allowed for Kidney-targeted Treatment of Cisplatin Induced Acute Kidney Injury

Introduction: Acute kidney injury (AKI) has a high mortality rate which can be partially attributed to inefficient renal delivery of therapeutic drugs. Nanoparticles are promising candidates in the development of theranostic agents for AKI since they can be made with controllable kidney targeting properties, such as kidney specificity and size control to make it past glomerular filtration. We developed a series of polyvinylpyrrolidone (PVP)-curcumin nanoparticles (PCurNP) as controllable delivery nanosystems which meet the renal excretion threshold of about 45 kDa for the purpose of treating AKI. They were analyzed for treatment of cisplatin-induced AKI. Since these nanoparticles can be imaged with positron emission tomography (PET), they make up a PET image-guided drug delivery system for the kidney.

Methods: PVP-curcumin nanoparticles were synthesized using PVP of molecular weights 10 kDa (M10), 29 kDa (M29), or 40 kDa (M40), each conjugated to curcumin. Nanoparticle formation was due to the hydrophobic interaction of curcumin inside the conjugates (forming PCurNP M10, PCurNP M29, and PCurNP M40). Cisplatin-induced AKI mouse models were established with intraperitoneal injections of cisplatin. in BALB/c mice with three groups: healthy, AKI, and AKI+treatment (n=3/group). Serum and renal tissue were collected to assess the development and treatment of AKI before treatment. At 2h after cisplatin injection, AKI+treatment mice were intravenously injected with PCurNP M10 and AKI was evaluated using a tubular injury score (TIS). For PET imaging, the nanoparticles were also radiolabeled with ⁸⁹Zr through mixing, with the oxygen donors of the PVP-curcumin conjugates being capable of chelation. BALB/c mice were injected in the tail vein with ⁸⁹Zr-PCurNP M10, M29, and M40, after which dynamic PET scans were taken for 30 min (n=3/group). Images were also taken at 1, 2, 3, 5, 14, and 24 h post injection (p.i.). For ex vivo validation of biodistribution results (24 h p.i.), major organs were harvested, weighed, and radioactivity was measured using a gamma counter. In vitro and in vivo biocompatibility studies were performed. Human embryonic kidney cells (HEK 293) were incubated with PCurNP at different concentrations for 24 h then cell viability was analyzed. Healthy male BALB/c mice were injected in the tail vein with PCurNP M10 to analyze the toxicity of these nanoparticles.

Results: In mice with cisplatin-induced AKI, PCurNP M10 were able to restore some kidney function, indicated by a lower TIS than in the control group. A score of either 0 or 1 was observed, where 0 indicates no lesions, 1 indicates swelling of tubular epithelial cells. In PET images, high kidney uptake was seen at all times, in addition to a significant signal in the bladder. At 2.25 min p.i., ⁸⁹Zr-PCurNP M10 uptake in the kidney was 36.4±13.9 %ID/g, and decreased to 16.7±4.6 %ID/g by 30 min. While M10 had higher kidney uptake than M40, the duration of blood circulation of M40 was higher than of M10. At 24 h p.i., the accumulation of M10 in the kidney was 15.4±0.3 %ID/g, which was about 1.7 times higher than that of M29 (6.3±0.1 %ID/g) and 1.8 times higher than that of M40 (5.7±1.2 %ID/g). Low accumulation was found in the liver (max 22.2±9.1 %ID/g) and spleen (max 14.4±2.2 %ID/g). These results agreed with the ex vivo biodistribution study. In the biocompatibility studies, PCurNPs were not found to be cytotoxic to HEK 293 cells nor to BALB/c mice.

Conclusions: We synthesized a nanoparticle delivery system for the kidney which meets the renal excretion threshold of about 45 kDa in order to treat AKI. Dynamic PET imaging has shown that these nanoparticles rapidly accumulate in the kidney as intended. They are not cytotoxic. The smallest of these nanoparticles, PCurNP M10, has been shown to have therapeutic efficacy against cisplatin-induced AKI. Due to their ability to be readily imaged with dynamic PET, they represent a viable image-guided drug delivery system for the kidney.

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