Integration of caveolin-mediated cytosolic delivery and enzyme-responsive releasing of squalenoyl nanoparticles enhance the anti-cancer efficacy of chidamide in pancreatic cancer
Copyright © 2024 Elsevier B.V. All rights reserved..
We explored the potential of overcoming the dense interstitial barrier in pancreatic cancer treatment by enhancing the uptake of hydrophilic chemotherapeutic drugs. In this study, we synthesized the squalenoyl-chidamide prodrug (SQ-CHI), linking lipophilic squalene (SQ) with the hydrophilic antitumor drug chidamide (CHI) through a trypsin-responsive bond. Self-assembled nanoparticles with sigma receptor-bound aminoethyl anisamide (AEAA) modification, forming AEAA-PEG-SQ-CHI NPs (A-C NPs, size 116.6 ± 0.4 nm), and reference nanoparticles without AEAA modification, forming mPEG-SQ-CHI NPs (M-C NPs, size 88.3 ± 0.3 nm), were prepared. A-C NPs exhibited significantly higher in vitro CHI release (74.7 %) in 0.5 % trypsin medium compared to release (20.2 %) in medium without trypsin. In vitro cell uptake assays revealed 3.6 and 2.3times higher permeation of A-C NPs into tumorspheres of PSN-1/HPSC or CFPAC-1/HPSC, respectively, compared to M-C NPs. Following intraperitoneal administration to subcutaneous tumor-bearing nude mice, the A-C NPs group demonstrated significant anti-pancreatic cancer efficacy, inducing cancer cell apoptosis and inhibiting proliferation in vivo. Mechanistic studies revealed that AEAA surface modification on nanoparticles promoted intracellular uptake through caveolin-mediated endocytosis. This nanoparticle system presents a novel therapeutic approach for pancreatic cancer treatment, offering a delivery strategy to enhance efficacy through improved tumor permeation, trypsin-responsive drug release, and specific cell surface receptor-mediated intracellular uptake.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:655 |
|---|---|
| Enthalten in: |
International journal of pharmaceutics - 655(2024) vom: 25. Apr., Seite 124072 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chen, Junyan [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 15.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ijpharm.2024.124072 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370506278 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370506278 | ||
| 003 | DE-627 | ||
| 005 | 20240415233629.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240403s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ijpharm.2024.124072 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1376.xml |
| 035 | |a (DE-627)NLM370506278 | ||
| 035 | |a (NLM)38561133 | ||
| 035 | |a (PII)S0378-5173(24)00306-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chen, Junyan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Integration of caveolin-mediated cytosolic delivery and enzyme-responsive releasing of squalenoyl nanoparticles enhance the anti-cancer efficacy of chidamide in pancreatic cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.04.2024 | ||
| 500 | |a Date Revised 15.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a We explored the potential of overcoming the dense interstitial barrier in pancreatic cancer treatment by enhancing the uptake of hydrophilic chemotherapeutic drugs. In this study, we synthesized the squalenoyl-chidamide prodrug (SQ-CHI), linking lipophilic squalene (SQ) with the hydrophilic antitumor drug chidamide (CHI) through a trypsin-responsive bond. Self-assembled nanoparticles with sigma receptor-bound aminoethyl anisamide (AEAA) modification, forming AEAA-PEG-SQ-CHI NPs (A-C NPs, size 116.6 ± 0.4 nm), and reference nanoparticles without AEAA modification, forming mPEG-SQ-CHI NPs (M-C NPs, size 88.3 ± 0.3 nm), were prepared. A-C NPs exhibited significantly higher in vitro CHI release (74.7 %) in 0.5 % trypsin medium compared to release (20.2 %) in medium without trypsin. In vitro cell uptake assays revealed 3.6 and 2.3times higher permeation of A-C NPs into tumorspheres of PSN-1/HPSC or CFPAC-1/HPSC, respectively, compared to M-C NPs. Following intraperitoneal administration to subcutaneous tumor-bearing nude mice, the A-C NPs group demonstrated significant anti-pancreatic cancer efficacy, inducing cancer cell apoptosis and inhibiting proliferation in vivo. Mechanistic studies revealed that AEAA surface modification on nanoparticles promoted intracellular uptake through caveolin-mediated endocytosis. This nanoparticle system presents a novel therapeutic approach for pancreatic cancer treatment, offering a delivery strategy to enhance efficacy through improved tumor permeation, trypsin-responsive drug release, and specific cell surface receptor-mediated intracellular uptake | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Aminoethyl anisamide | |
| 650 | 4 | |a Caveolin mediated pathway | |
| 650 | 4 | |a Pancreatic cancer | |
| 650 | 4 | |a Permeability | |
| 650 | 4 | |a Squalenoyl-chidamide prodrug | |
| 650 | 7 | |a N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide |2 NLM | |
| 650 | 7 | |a 87CIC980Y0 |2 NLM | |
| 650 | 7 | |a Caveolins |2 NLM | |
| 650 | 7 | |a Trypsin |2 NLM | |
| 650 | 7 | |a EC 3.4.21.4 |2 NLM | |
| 650 | 7 | |a Prodrugs |2 NLM | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 700 | 1 | |a Chen, Kaidi |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Shuai |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Yuwei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hangjie |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Guilin |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Mu, Chaofeng |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Mancang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of pharmaceutics |d 1992 |g 655(2024) vom: 25. Apr., Seite 124072 |w (DE-627)NLM07779785X |x 1873-3476 |7 nnns |
| 773 | 1 | 8 | |g volume:655 |g year:2024 |g day:25 |g month:04 |g pages:124072 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ijpharm.2024.124072 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 655 |j 2024 |b 25 |c 04 |h 124072 | ||