Prevention of cisplatin-induced nephrotoxicity by kidney-targeted siRNA delivery

AYDIN E., CEBECİ AYDIN A., LEKESİZCAN A.

INTERNATIONAL JOURNAL OF PHARMACEUTICS, cilt.628, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 628
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.ijpharm.2022.122268
  • Dergi Adı: INTERNATIONAL JOURNAL OF PHARMACEUTICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Cisplatin, Nephrotoxicity, siRNA, Kidney -targeted delivery, Chitosan, Nanoparticles, ORGANIC CATION TRANSPORTER-2, HIGH-DOSE CISPLATIN, CHITOSAN NANOPARTICLES, COPPER TRANSPORTER, RENAL INJURY, MECHANISMS, CIMETIDINE, OCT2, INHIBITION, APOPTOSIS
  • Abdullah Gül Üniversitesi Adresli: Evet

Özet

Cisplatin is a potent and widely used chemotherapy agent, however, nephrotoxicity limits its use. Many patients need to pause or withdraw from chemotherapy to prevent acute kidney injury. To prevent cisplatin damage, we designed chitosan/siRNA nanoparticleswhich are nontoxic and are readily taken up by HEK293 cells. The nanoparticles contained siRNA against cationic membrane transport (OCT1&2) and apoptosis related proteins (p53, PKC8, and gamma GT). In mice treated with cisplatin, serum creatinine levels increased from 15 to 88 mg/dL and blood urea nitrogen levels increased from 0.25 to 1.7 mg/dL, however, siRNA nanoparticles significantly limited these levels to 30 mg/dL and 0.55 mg/dL, respectively. Western and IHC analyses showed lower p53, PKC8, and gamma GT expressions in siRNA treated mice. Histomorphological evaluation revealed high-level protection of kidney proximal tubules from cisplatin damage. Protein expressions and extent of kidney protection were directly correlated with number of siRNA applications. Our results suggest that this novel approach for kidney -targeted delivery of select siRNAs may represent a promising therapy for preventing cisplatin-induced nephro-toxicity. Furthermore, this or other similarly sized nanocarriers could potentially be utilized to passively target kidneys for diagnostic, protective, or treatment purposes.