CAPN2-responsive mesoporous silica nanoparticles: A promising nanocarrier for targeted therapy of pancreatic cancer

Pancreatic adenocarcinoma (PDAC) is highly resistant to conventional chemotherapeutic interventions, resulting in exceptionally low survival rates. The limited efficacy can in part be attributed to dose limitations and treatment cessation urged by toxicity of currently used chemotherapy. The advent...

Full description

Saved in:
Bibliographic Details
Published in:Cancer letters 2024-05, Vol.590, p.216845-216845, Article 216845
Main Authors: Slapak, Etienne J., el Mandili, Mouad, Ten Brink, Marieke S., Kros, Alexander, Bijlsma, Maarten F., Spek, C. Arnold
Format: Article
Language:English
Subjects:
ADAM9
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - metabolism
Animals
Antitumor
BACE2
Calpain - metabolism
CAPN2
Cell Line, Tumor
DPP3
Drug Carriers - chemistry
Drug delivery
Female
Humans
Leukopenia
Mice
Mice, Nude
MSN
Nanoparticles - chemistry
Neurotoxicity
Paclitaxel - administration & dosage
Paclitaxel - pharmacology
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - pathology
PDAC
Porosity
Silicon Dioxide - chemistry
Targeted therapy
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Pancreatic adenocarcinoma (PDAC) is highly resistant to conventional chemotherapeutic interventions, resulting in exceptionally low survival rates. The limited efficacy can in part be attributed to dose limitations and treatment cessation urged by toxicity of currently used chemotherapy. The advent of targeted delivery strategies has kindled hope for circumventing off-target toxicity. We have previously reported a PDAC-specific mesoporous silica nanoparticle (MSN) containing a protease linker responsive to ADAM9, a PDAC-enriched extracellularly deposited protease. Upon loading with paclitaxel these ADAM9-MSNs reduced side effects both in vitro and in vivo, however, disappointing antitumor efficacy was observed in vivo. Here, we propose that an efficient uptake of MSNs by tumor cells might underlie the lack of antitumor efficacy of MSNs functionalized with linker responsive to extracellular proteases. Harnessing this premise to improve antitumor efficacy, we performed an in silico analysis to identify PDAC-enriched intracellular proteases. We report the identification of BACE2, CAPN2 and DPP3 as PDAC enriched intracellular proteases, and report the synthesis of BACE2-, CAPN2- and DPP3-responsive MSNs. Extensive preclinical assessments revealed that paclitaxel-loaded CAPN2- and DPP3-MSNs exhibit high PDAC specificity in vitro as opposed to free paclitaxel. The administration of paclitaxel-loaded CAPN2- and DPP3-MSNs in vivo confirmed the reduction of leukopenia and induced no organ damage. Promisingly, in two mouse models CAPN2-MSNs reduced tumor growth at least as efficiently as free paclitaxel. Taken together, our results pose CAPN2-MSNs as a promising nanocarrier for the targeted delivery of chemotherapeutics in PDAC. •MSNs are efficiently taken up by PDAC cells.•BACE2, CAPN2, DPP3, PRSS23 and STAMBPL1 are PDAC-enriched proteases.•Paclitaxel-loaded CAPN2 and DPP3-responsive MSNs show high cytotoxicity in PDAC, while reducing leukopenia and neurotoxicity in vitro.•CAPN2-responsive MSNs harbor superior antitumor efficacy compared to systemically administered paclitaxel and nab-paclitaxel in vivo.•CAPN2-responsive MSNs reduce leukopenia and do not cause organ damage compared to systemic paclitaxel administration in vivo.•CAPN2-responsive MSNs are promising nanocarriers for the targeted delivery of chemotherapeutics in PDAC.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2024.216845