Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration
Rui Ni,1– 3 Lele Huang,3 Zhen Li,4 Wenli Zhang,4 Yajie Wang,4 Yan Shen,4 Jianxin Wang,1 Weigen Lu2 1School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2China State Institute of Pharmaceutical Industry, Shanghai, People’s Republic of China; 3National Advanced Medical Engineer...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2022-12-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/multifunctional-ros-responsive-and-tme-modulated-lipid-polymer-hybrid--peer-reviewed-fulltext-article-IJN |
| _version_ | 1797963383637540864 |
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| author | Ni R Huang L Li Z Zhang W Wang Y Shen Y Wang J Lu W |
| author_facet | Ni R Huang L Li Z Zhang W Wang Y Shen Y Wang J Lu W |
| author_sort | Ni R |
| collection | DOAJ |
| description | Rui Ni,1– 3 Lele Huang,3 Zhen Li,4 Wenli Zhang,4 Yajie Wang,4 Yan Shen,4 Jianxin Wang,1 Weigen Lu2 1School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2China State Institute of Pharmaceutical Industry, Shanghai, People’s Republic of China; 3National Advanced Medical Engineering Research Center, Shanghai, People’s Republic of China; 4Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaCorrespondence: Jianxin Wang, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China, Email jxwang@shmu.edu.cn Weigen Lu, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People’s Republic of China, Email sipiluwg@163.comPurpose: To enhance tumor penetration by formulation design and tumor microenvironment (TME) modulation, herein a novel reactive oxygen species (ROS)-responsive size/shape transformable lipid-polymer hybrid nanoparticle (LPN) has been fabricated for the co-delivery of an anticancer and collagen-inhibition drug.Methods: A ROS-responsive poly(D, L-lactide)-thioketal-polyethylene glycol (PLA-TK-PEG) co-polymer was synthesized. LPNs were then fabricated by encapsulation of losartan (LST)-loaded micelles as the core to support paclitaxel (PTX)-loaded liposomes. The PEG content in the lipid shell of LPNs was then adjusted to obtain the size-/shape-transformable LPNs (M/LST-Lip/PTX-PEG5%). The ROS-responsiveness was observed in vitro by transmission electron microscopy and the tumor-penetration of the LPNs was evaluated in 3D tumor spheroids by confocal laser scanning microscopy. Tumor-targeting, tumor-penetrating, and antitumor efficacies of the NPs in 4T1 tumor-bearing mice were determined by in vivo imaging.Results: ROS-responsive micellar core degradation and the transformation of spherical LPNs (120nm) to smaller 40 mm discoid nanoparticles (NP) were observed. The transformable LPNs exhibited enhanced capacity of penetration in contrast to the un-transformable preparations in three-dimensional (3D) tumor spheroids. Furthermore, synergetic penetrating enhancement was achieved by LST-loaded transformable LPNs in 4T1 and fibroblast cell mixed 3D tumor spheroids. The improved tumor penetration of LST-loaded transformable LPNs was observed in vivo, which could be due to their collagen inhibiting and size/shape transformable effect. Due to their enhanced penetrability, LST and PTX-loaded transformable LPNs demonstrated significant in vivo antitumor efficacy in comparison to other preparations.Conclusion: The results confirmed the efficacy of M/LST-Lip/PTX-PEG5% in tumor targeting, collagen inhibition in TME, and enhanced tumor penetration. This novel drug delivery system can therefore play a substantial role in improving the therapeutic efficacy of antitumor drugs combined with TME-improving agents.Keywords: lipid-polymer hybrid nanoparticles, losartan, paclitaxel, ROS responsiveness, drug delivery, collagen inhibition, tumor penetration, combination therapy |
| first_indexed | 2024-04-11T01:27:29Z |
| format | Article |
| id | doaj.art-bf02bed5e3a64e5082ef27c6aa92ade2 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-04-11T01:27:29Z |
| publishDate | 2022-12-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-bf02bed5e3a64e5082ef27c6aa92ade22023-01-03T10:09:29ZengDove Medical PressInternational Journal of Nanomedicine1178-20132022-12-01Volume 175883589780028Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor PenetrationNi RHuang LLi ZZhang WWang YShen YWang JLu WRui Ni,1– 3 Lele Huang,3 Zhen Li,4 Wenli Zhang,4 Yajie Wang,4 Yan Shen,4 Jianxin Wang,1 Weigen Lu2 1School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2China State Institute of Pharmaceutical Industry, Shanghai, People’s Republic of China; 3National Advanced Medical Engineering Research Center, Shanghai, People’s Republic of China; 4Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaCorrespondence: Jianxin Wang, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China, Email jxwang@shmu.edu.cn Weigen Lu, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People’s Republic of China, Email sipiluwg@163.comPurpose: To enhance tumor penetration by formulation design and tumor microenvironment (TME) modulation, herein a novel reactive oxygen species (ROS)-responsive size/shape transformable lipid-polymer hybrid nanoparticle (LPN) has been fabricated for the co-delivery of an anticancer and collagen-inhibition drug.Methods: A ROS-responsive poly(D, L-lactide)-thioketal-polyethylene glycol (PLA-TK-PEG) co-polymer was synthesized. LPNs were then fabricated by encapsulation of losartan (LST)-loaded micelles as the core to support paclitaxel (PTX)-loaded liposomes. The PEG content in the lipid shell of LPNs was then adjusted to obtain the size-/shape-transformable LPNs (M/LST-Lip/PTX-PEG5%). The ROS-responsiveness was observed in vitro by transmission electron microscopy and the tumor-penetration of the LPNs was evaluated in 3D tumor spheroids by confocal laser scanning microscopy. Tumor-targeting, tumor-penetrating, and antitumor efficacies of the NPs in 4T1 tumor-bearing mice were determined by in vivo imaging.Results: ROS-responsive micellar core degradation and the transformation of spherical LPNs (120nm) to smaller 40 mm discoid nanoparticles (NP) were observed. The transformable LPNs exhibited enhanced capacity of penetration in contrast to the un-transformable preparations in three-dimensional (3D) tumor spheroids. Furthermore, synergetic penetrating enhancement was achieved by LST-loaded transformable LPNs in 4T1 and fibroblast cell mixed 3D tumor spheroids. The improved tumor penetration of LST-loaded transformable LPNs was observed in vivo, which could be due to their collagen inhibiting and size/shape transformable effect. Due to their enhanced penetrability, LST and PTX-loaded transformable LPNs demonstrated significant in vivo antitumor efficacy in comparison to other preparations.Conclusion: The results confirmed the efficacy of M/LST-Lip/PTX-PEG5% in tumor targeting, collagen inhibition in TME, and enhanced tumor penetration. This novel drug delivery system can therefore play a substantial role in improving the therapeutic efficacy of antitumor drugs combined with TME-improving agents.Keywords: lipid-polymer hybrid nanoparticles, losartan, paclitaxel, ROS responsiveness, drug delivery, collagen inhibition, tumor penetration, combination therapyhttps://www.dovepress.com/multifunctional-ros-responsive-and-tme-modulated-lipid-polymer-hybrid--peer-reviewed-fulltext-article-IJNlipid-polymer hybrid nanoparticleslosartanpaclitaxelros responsivenessdrug deliverycollagen inhibitiontumor penetrationcombination therapy. |
| spellingShingle | Ni R Huang L Li Z Zhang W Wang Y Shen Y Wang J Lu W Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration International Journal of Nanomedicine lipid-polymer hybrid nanoparticles losartan paclitaxel ros responsiveness drug delivery collagen inhibition tumor penetration combination therapy. |
| title | Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration |
| title_full | Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration |
| title_fullStr | Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration |
| title_full_unstemmed | Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration |
| title_short | Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration |
| title_sort | multifunctional ros responsive and tme modulated lipid polymer hybrid nanoparticles for enhanced tumor penetration |
| topic | lipid-polymer hybrid nanoparticles losartan paclitaxel ros responsiveness drug delivery collagen inhibition tumor penetration combination therapy. |
| url | https://www.dovepress.com/multifunctional-ros-responsive-and-tme-modulated-lipid-polymer-hybrid--peer-reviewed-fulltext-article-IJN |
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