Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment
Copyright © 2024 Elsevier Inc. All rights reserved..
Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:665 |
|---|---|
| Enthalten in: |
Journal of colloid and interface science - 665(2024) vom: 10. Apr., Seite 477-490 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Qiao, Jianan [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 17.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jcis.2024.02.141 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369189957 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369189957 | ||
| 003 | DE-627 | ||
| 005 | 20240417232549.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240302s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jcis.2024.02.141 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1378.xml |
| 035 | |a (DE-627)NLM369189957 | ||
| 035 | |a (NLM)38429120 | ||
| 035 | |a (PII)S0021-9797(24)00385-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Qiao, Jianan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment |
| 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 17.04.2024 | ||
| 500 | |a Date Revised 17.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Inc. All rights reserved. | ||
| 520 | |a Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Integrated smart nanodrug delivery | |
| 650 | 4 | |a KRAS mutational associated metabolic reprogramming | |
| 650 | 4 | |a Multidimensional metabolic modulation | |
| 650 | 4 | |a Pancreatic ductal adenocarcinoma | |
| 650 | 4 | |a Photodynamic therapy | |
| 650 | 7 | |a Glutamine |2 NLM | |
| 650 | 7 | |a 0RH81L854J |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Phosphatidylinositol 3-Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.1.- |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.12.2 |2 NLM | |
| 700 | 1 | |a Liu, Shuhui |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yanfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Chenyang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Jing |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of colloid and interface science |d 1966 |g 665(2024) vom: 10. Apr., Seite 477-490 |w (DE-627)NLM041487958 |x 1095-7103 |7 nnns |
| 773 | 1 | 8 | |g volume:665 |g year:2024 |g day:10 |g month:04 |g pages:477-490 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jcis.2024.02.141 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 665 |j 2024 |b 10 |c 04 |h 477-490 | ||