Combined Ibuprofen-Nanoconjugate Micelles with E-Selectin for Effective Sunitinib Anticancer Therapy

Int J Nanomedicine. 2022 Dec 6:17:6031-6046. doi: 10.2147/IJN.S388234. eCollection 2022.

Abstract

Introduction: Sunitinib, a first-line therapy with a certain effect, was utilized in the early stages of renal cell carcinoma treatment. However, its clinical toxicity, side effects, and its limited bioavailability, resulted in inadequate clinical therapeutic efficacy. Building neoteric, simple, and safe drug delivery systems with existing drugs offers new options. Therefore, we aimed to construct a micelle to improve the clinical efficacy of sunitinib by reusing ibuprofen.

Methods: We synthesized the sialic acid-poly (ethylene glycol)-ibuprofen (SA-PEG-IBU) amphipathic conjugate in two-step reaction. The SA-PEG-IBU amphiphilic conjugates can form into stable SPI nanomicelles in aqueous solution, which can be further loaded sunitinib (SU) to obtain the SPI/SU system. Following nanomicelle creation, sialic acid exposed to the nanomicelle surface can recognize the overexpressed E-selectin receptor on the membrane of cancer cells to enhance cellular uptake. The properties of morphology, stability, and drug release about the SPI/SU nanomicelles were investigated. Confocal microscopy and flow cytometry were used to assess the cellular uptake efficiency of nanomicelles in vitro. Finally, a xenograft tumor model in nude mice was constructed to investigate the body distribution and tumor suppression of SPI/SU in vivo.

Results: The result showed that SPI nanomicelles exhibited excellent tumor targeting performance and inhibited the migration and invasion of tumor cell in vitro. The SPI nanomicelles can improve the accumulation of drugs in the tumor site that showed effective tumor inhibition in vivo. In addition, H&E staining and immunohistochemical analysis demonstrated that the SPI/SU nanomicelles had a superior therapeutic effect and lower biotoxicity.

Conclusion: The SPI/SU nanomicelles displayed excellent anti-tumor ability, and can suppress the metastasis of tumor cell by decreasing the expression of Cyclooxygenase-2 due to the ibuprofen, providing an optimistic clinical application potential by developing a simple but safe drug delivery system.

Keywords: anti-tumor therapy; ibuprofen; kidney cancer; nanomicelles; sialic acid; sunitinib.

MeSH terms

  • Animals
  • Carcinoma, Renal Cell*
  • Cell Line, Tumor
  • Drug Carriers / chemistry
  • Humans
  • Ibuprofen
  • Kidney Neoplasms*
  • Mice
  • Mice, Nude
  • Micelles
  • N-Acetylneuraminic Acid
  • Nanoconjugates
  • Polyethylene Glycols / chemistry
  • Sunitinib

Substances

  • Micelles
  • Sunitinib
  • Nanoconjugates
  • N-Acetylneuraminic Acid
  • Ibuprofen
  • Polyethylene Glycols
  • Drug Carriers