Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most feared diseases worldwide owing to its poor prognosis, negligible therapeutic advances, and high mortality. Herein, multifunctional enzyme-responsive micelles for the controlled delivery of paclitaxel (PTX) were prepared to circumvent i...
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Elsevier
2025-04-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425001139 |
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| author | Diana Peixoto João M. Ravasco Barbara Blanco-Fernandez Francisco Veiga Angel Concheiro João Conde Ana Cláudia Paiva-Santos Carmen Alvarez-Lorenzo |
| author_facet | Diana Peixoto João M. Ravasco Barbara Blanco-Fernandez Francisco Veiga Angel Concheiro João Conde Ana Cláudia Paiva-Santos Carmen Alvarez-Lorenzo |
| author_sort | Diana Peixoto |
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| description | Pancreatic ductal adenocarcinoma (PDAC) remains one of the most feared diseases worldwide owing to its poor prognosis, negligible therapeutic advances, and high mortality. Herein, multifunctional enzyme-responsive micelles for the controlled delivery of paclitaxel (PTX) were prepared to circumvent its current clinical challenges. Accordingly, two enzyme-responsive structural units composed of Vitamin D3 (VD3) conjugated with polyethylene glycol of different molecular weights (600 Da and 2000 Da) were synthesized and characterized using different analytical methods. By applying the solvent evaporation method, these bioactive structural units self-assembled into sub-100 nm VD3 micelles with minimal batch-to-batch variation, monomodal particle size distribution, and high encapsulation efficiency. The enzyme-triggered disassembly of PTX-loaded VD3 micelles was demonstrated by release studies in the presence of a high esterase content typically featured by PDAC cells. PTX-loaded VD3 micelles also exhibited prominent cell internalization and induced a considerable cytotoxic synergistic effect against human PDAC cells (BxPC-3 cells) in 2D and 3D cell culture models compared with free PTX. The PTX-loaded VD3 micelles were hemocompatible and stable after long-term storage in the presence of biorelevant media, and showed higher efficiency to inhibit the tumor growth compared to the approved clinical nanoformulation (Abraxane®) in an in ovo tumor model. The findings reported here indicate that VD3S-PEG micelles may have a promising role in PDAC therapy, since VD3 could act not only as a hydrophobic core of the micelles but also as a therapeutic agent that provides synergetic therapeutic effects with the encapsulated PTX. |
| format | Article |
| id | doaj-art-52b60263a15a4d7282c54130c255a6f4 |
| institution | Kabale University |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | Materials Today Bio |
| spelling | doaj-art-52b60263a15a4d7282c54130c255a6f42025-02-12T05:31:42ZengElsevierMaterials Today Bio2590-00642025-04-0131101555Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapyDiana Peixoto0João M. Ravasco1Barbara Blanco-Fernandez2Francisco Veiga3Angel Concheiro4João Conde5Ana Cláudia Paiva-Santos6Carmen Alvarez-Lorenzo7Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782, Santiago, SpainComprehensive Health Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169, Lisboa, Portugal; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649, Lisbon, PortugalDepartamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782, Santiago, SpainDepartment of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, PortugalDepartamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782, Santiago, SpainComprehensive Health Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169, Lisboa, Portugal; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649, Lisbon, Portugal; Corresponding author. Comprehensive Health Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169, Lisboa, Portugal.Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; Corresponding author. Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal.Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782, Santiago, Spain; Corresponding author. Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.Pancreatic ductal adenocarcinoma (PDAC) remains one of the most feared diseases worldwide owing to its poor prognosis, negligible therapeutic advances, and high mortality. Herein, multifunctional enzyme-responsive micelles for the controlled delivery of paclitaxel (PTX) were prepared to circumvent its current clinical challenges. Accordingly, two enzyme-responsive structural units composed of Vitamin D3 (VD3) conjugated with polyethylene glycol of different molecular weights (600 Da and 2000 Da) were synthesized and characterized using different analytical methods. By applying the solvent evaporation method, these bioactive structural units self-assembled into sub-100 nm VD3 micelles with minimal batch-to-batch variation, monomodal particle size distribution, and high encapsulation efficiency. The enzyme-triggered disassembly of PTX-loaded VD3 micelles was demonstrated by release studies in the presence of a high esterase content typically featured by PDAC cells. PTX-loaded VD3 micelles also exhibited prominent cell internalization and induced a considerable cytotoxic synergistic effect against human PDAC cells (BxPC-3 cells) in 2D and 3D cell culture models compared with free PTX. The PTX-loaded VD3 micelles were hemocompatible and stable after long-term storage in the presence of biorelevant media, and showed higher efficiency to inhibit the tumor growth compared to the approved clinical nanoformulation (Abraxane®) in an in ovo tumor model. The findings reported here indicate that VD3S-PEG micelles may have a promising role in PDAC therapy, since VD3 could act not only as a hydrophobic core of the micelles but also as a therapeutic agent that provides synergetic therapeutic effects with the encapsulated PTX.http://www.sciencedirect.com/science/article/pii/S2590006425001139Pancreatic ductal adenocarcinomaBioactive vitamin D3 conjugateEsterase-activatable micelleIntracellular drug deliveryPaclitaxel |
| spellingShingle | Diana Peixoto João M. Ravasco Barbara Blanco-Fernandez Francisco Veiga Angel Concheiro João Conde Ana Cláudia Paiva-Santos Carmen Alvarez-Lorenzo Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy Materials Today Bio Pancreatic ductal adenocarcinoma Bioactive vitamin D3 conjugate Esterase-activatable micelle Intracellular drug delivery Paclitaxel |
| title | Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy |
| title_full | Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy |
| title_fullStr | Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy |
| title_full_unstemmed | Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy |
| title_short | Enzyme-responsive vitamin D-based micelles for paclitaxel-controlled delivery and synergistic pancreatic cancer therapy |
| title_sort | enzyme responsive vitamin d based micelles for paclitaxel controlled delivery and synergistic pancreatic cancer therapy |
| topic | Pancreatic ductal adenocarcinoma Bioactive vitamin D3 conjugate Esterase-activatable micelle Intracellular drug delivery Paclitaxel |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425001139 |
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