Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carri...
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Elsevier
2024-10-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006424002606 |
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| author | Naga Malleswara Rao Nakka Hari Krishnareddy Rachamala Ramcharan Singh Angom Nagamalleswara Rao Indla Shamit Kumar Dutta Enfeng Wang Santanu Bhattacharya Annadanam V. Sesha Sainath Hani Babiker Krishnendu Pal Debabrata Mukhopadhyay |
| author_facet | Naga Malleswara Rao Nakka Hari Krishnareddy Rachamala Ramcharan Singh Angom Nagamalleswara Rao Indla Shamit Kumar Dutta Enfeng Wang Santanu Bhattacharya Annadanam V. Sesha Sainath Hani Babiker Krishnendu Pal Debabrata Mukhopadhyay |
| author_sort | Naga Malleswara Rao Nakka |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carrier would be a favorable approach to overcome these limitations. Hence, a tumor-targeted peptide (TTP) conjugated amphiphilic tri-block copolymer was developed to make targeted polymer nanoparticles (TTP-PNPs) serving as a vehicle for carrying gemcitabine (Gem), paclitaxel (PTX), and their combination (Gem + PTX). The TTP-PNPs in the form of empty polymer (P), single drug-loaded [P(Gem) and P(PTX)], and dual drug-loaded [P(Gem + PTX)] polymer nanoformulations exhibited stable and homogenous spherical shapes with 110–160 nm size. These nanoformulations demonstrated excellent stability under in vitro physiological conditions and led to an efficient release of the drugs in the presence of reduced glutathione (GSH). The efficacy of these nanoparticles was thoroughly evaluated in vitro and in vivo, demonstrating a notable capacity to selectively target and restrict PDAC cells (PANC-1 and KPC) growth. The cellular uptake and biodistribution study showed a significantly higher tumor-targeting ability of TTP-PNPs than PNPs without TTP. Notably, P(Gem + PTX) exhibited the lowest IC50 compared to all other controls and showed heightened synergistic effects in both cell lines. Furthermore, P(Gem + PTX) showed a significantly better tumor reduction and median overall survival in mouse models than single drug-loaded TTP-PNPs or a combination of free drugs (Gem + PTX). In summary, our TTP-PNP system shows great promise as a novel platform for delivering Gem + PTX specifically to pancreatic cancer (PC), maximizing the therapeutic benefits with lower concentrations of the drugs and potentially reducing toxic side effects. |
| format | Article |
| id | doaj-art-af4e9d5dd2c4413bb0f9e1232ea4f2ba |
| institution | OA Journals |
| issn | 2590-0064 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-af4e9d5dd2c4413bb0f9e1232ea4f2ba2025-08-20T01:54:45ZengElsevierMaterials Today Bio2590-00642024-10-012810119910.1016/j.mtbio.2024.101199Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinomaNaga Malleswara Rao Nakka0Hari Krishnareddy Rachamala1Ramcharan Singh Angom2Nagamalleswara Rao Indla3Shamit Kumar Dutta4Enfeng Wang5Santanu Bhattacharya6Annadanam V. Sesha Sainath7Hani Babiker8Krishnendu Pal9Debabrata Mukhopadhyay10Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USAPolymers and Functional Materials and Fluoro-Agrochemicals Department, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, IndiaDepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USAPolymers and Functional Materials and Fluoro-Agrochemicals Department, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, IndiaDepartment of Medicine, Division of Hematology-Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USADepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USA; Corresponding author. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Sciences, Jacksonville, FL, 32224, USA.Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carrier would be a favorable approach to overcome these limitations. Hence, a tumor-targeted peptide (TTP) conjugated amphiphilic tri-block copolymer was developed to make targeted polymer nanoparticles (TTP-PNPs) serving as a vehicle for carrying gemcitabine (Gem), paclitaxel (PTX), and their combination (Gem + PTX). The TTP-PNPs in the form of empty polymer (P), single drug-loaded [P(Gem) and P(PTX)], and dual drug-loaded [P(Gem + PTX)] polymer nanoformulations exhibited stable and homogenous spherical shapes with 110–160 nm size. These nanoformulations demonstrated excellent stability under in vitro physiological conditions and led to an efficient release of the drugs in the presence of reduced glutathione (GSH). The efficacy of these nanoparticles was thoroughly evaluated in vitro and in vivo, demonstrating a notable capacity to selectively target and restrict PDAC cells (PANC-1 and KPC) growth. The cellular uptake and biodistribution study showed a significantly higher tumor-targeting ability of TTP-PNPs than PNPs without TTP. Notably, P(Gem + PTX) exhibited the lowest IC50 compared to all other controls and showed heightened synergistic effects in both cell lines. Furthermore, P(Gem + PTX) showed a significantly better tumor reduction and median overall survival in mouse models than single drug-loaded TTP-PNPs or a combination of free drugs (Gem + PTX). In summary, our TTP-PNP system shows great promise as a novel platform for delivering Gem + PTX specifically to pancreatic cancer (PC), maximizing the therapeutic benefits with lower concentrations of the drugs and potentially reducing toxic side effects.http://www.sciencedirect.com/science/article/pii/S2590006424002606Pancreatic ductal adenocarcinomaTumor-targeted therapyAmphiphilic tri-block copolymerGemcitabinePaclitaxelPolymer nanoparticles |
| spellingShingle | Naga Malleswara Rao Nakka Hari Krishnareddy Rachamala Ramcharan Singh Angom Nagamalleswara Rao Indla Shamit Kumar Dutta Enfeng Wang Santanu Bhattacharya Annadanam V. Sesha Sainath Hani Babiker Krishnendu Pal Debabrata Mukhopadhyay Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma Materials Today Bio Pancreatic ductal adenocarcinoma Tumor-targeted therapy Amphiphilic tri-block copolymer Gemcitabine Paclitaxel Polymer nanoparticles |
| title | Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| title_full | Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| title_fullStr | Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| title_short | Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| title_sort | dual drug loaded tumor targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma |
| topic | Pancreatic ductal adenocarcinoma Tumor-targeted therapy Amphiphilic tri-block copolymer Gemcitabine Paclitaxel Polymer nanoparticles |
| url | http://www.sciencedirect.com/science/article/pii/S2590006424002606 |
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