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Direct Drug Delivery to Kidney via the Renal Artery
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Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Samuele Cazzamalli1, Alberto Dal Corso1, Dario Neri2

  • 1Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich (Switzerland).

Molecular Cancer Therapeutics
|September 10, 2016
PubMed

Insights

Acetazolamide derivatives target carbonic anhydrase IX (CAIX) on kidney cancer cells, selectively delivering cytotoxic drugs to tumors and sparing healthy organs. This targeted approach shows potent antitumor activity in preclinical models.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Delivery

Background:

  • Cytotoxic drugs often cause toxicity due to non-specific distribution, limiting therapeutic efficacy in cancer treatment.
  • Targeted drug delivery systems are needed to improve the therapeutic index of potent anticancer agents.
  • Carbonic anhydrase IX (CAIX) is a tumor-associated antigen overexpressed in clear cell renal cell carcinoma (ccRCC).

Purpose of the Study:

  • To develop and evaluate acetazolamide derivatives as targeted delivery agents for kidney cancer.
  • To assess the biodistribution, tumor accumulation, and antitumor activity of acetazolamide-based drug conjugates.

Main Methods:

  • Synthesis of acetazolamide derivatives conjugated to imaging agents (technetium-99m, red fluorophore) or cytotoxic drugs (MMAE, PNU-159682).
  • Biodistribution studies in tumor-bearing mice to determine tumor accumulation and organ distribution.
  • Antitumor efficacy studies in mice bearing human renal cell carcinoma xenografts (SKRC-52).

Main Results:

  • Acetazolamide derivatives demonstrated preferential accumulation in tumors, with optimal tumor:organ ratios achieved at specific doses.
  • Acetazolamide-drug conjugates exhibited potent antitumor activity, leading to tumor regression in preclinical models.
  • Drug conjugates lacking the acetazolamide moiety showed no significant anticancer activity, confirming the role of targeted delivery.

Conclusions:

  • Acetazolamide derivatives effectively target CAIX-expressing kidney cancer cells, enabling selective delivery of cytotoxic payloads.
  • The mechanism involves extracellular drug release followed by tumor cell internalization, leading to potent anticancer effects.
  • Acetazolamide-based drug conjugates represent a promising targeted therapeutic strategy for metastatic kidney cancer.

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