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  4. Tumor-specific targeting of a mitochondrial Kv1.3 channel inhibitor through conjugation to gastrin/cholecystokinin B receptor ligand strongly reduces pancreatic ductal adenocarcinoma in orthotopic models

Tumor-specific targeting of a mitochondrial Kv1.3 channel inhibitor through conjugation to gastrin/cholecystokinin B receptor ligand strongly reduces pancreatic ductal adenocarcinoma in orthotopic models  (2026)

Authors:
Parrasia, Sofia; Paoli, Carlotta; Varanita, Tatiana; Brillo, Valentina; Abdel-Salam, Mostafa A L; Ongaro, Alberto; Hornisch, Claudia; Angi, Beatrice; Bachmann, Magdalena; Bergamin, Filippo; Corbo, Vincenzo; Fiorini, Elena; Rossa, Andrea; Bossio, Giovanna; Gulbins, Erich; Carrer, Alessandro; Zoratti, Mario; Mattarei, Andrea; Ruzza, Paolo; Biasutto, Lucia; Szabo, Ildiko
Title:
Tumor-specific targeting of a mitochondrial Kv1.3 channel inhibitor through conjugation to gastrin/cholecystokinin B receptor ligand strongly reduces pancreatic ductal adenocarcinoma in orthotopic models
Year:
2026
Type of item:
Articolo in Rivista
Tipologia ANVUR:
Articolo su rivista
Language:
Inglese
Format:
Elettronico
Referee:
No
Name of journal:
Pharmacological Research
ISSN of journal:
1043-6618
N° Volume:
225
Page numbers:
1-20
Keyword:
Kv1.3 channel; mitochondria; pancreatic cancer; tumor-targeting peptides
Short description of contents:
: Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant and immunoresistant tumor with an overall five-year survival rate of less than 10%. Current treatments for PDAC are rather limited, highlighting the importance of finding novel strategies. In this study, we investigated a strategy for the tumor-specific targeting of PAPTP, a small molecule that reduces PDAC growth by inhibiting the mitochondrial potassium channel mtKv1.3, thereby inducing mitochondrial dysfunction and killing cancer cells. PAPTP was reversibly conjugated to three tumor-penetrating peptides: iRGD, VH434, and a short version of minigastrin (CCK2p). These recognize neuropilin-1 and integrin (iRGD), the low-density lipoprotein receptor (VH434), and the gastrin/cholecystokinin B receptor (CCK2p). In vivo pharmacokinetic studies revealed that the PAPTP-bound iRGD peptide underwent rapid metabolic cleavage, which prevented optimal uptake of the construct into PDAC. The VH434 conjugate was highly hemolytic. However, CCK2p-PAPTP exhibited preferential distribution to the pancreas in animals bearing orthotopic PDAC. Efficacy studies revealed a reduction in mean tumor volume of up to 65% in two independent orthotopic mouse models, with no tumor evident in some of the animals treated with the CCK2p-boundPAPTP construct. Our data suggest that tumor-specific targeting of small molecules may be a promising strategy for precision medicine against PDAC.
Note:
Available online 20 February 2026
Product ID:
150046
Handle IRIS:
11562/1184269
Last Modified:
March 15, 2026
Bibliographic citation:
Parrasia, Sofia; Paoli, Carlotta; Varanita, Tatiana; Brillo, Valentina; Abdel-Salam, Mostafa A L; Ongaro, Alberto; Hornisch, Claudia; Angi, Beatrice; Bachmann, Magdalena; Bergamin, Filippo; Corbo, Vincenzo; Fiorini, Elena; Rossa, Andrea; Bossio, Giovanna; Gulbins, Erich; Carrer, Alessandro; Zoratti, Mario; Mattarei, Andrea; Ruzza, Paolo; Biasutto, Lucia; Szabo, Ildiko, Tumor-specific targeting of a mitochondrial Kv1.3 channel inhibitor through conjugation to gastrin/cholecystokinin B receptor ligand strongly reduces pancreatic ductal adenocarcinoma in orthotopic models «Pharmacological Research» , vol. 225 , 2026 , pp. 1-20

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo IRIS

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