A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis
Yu Hsia,1,2 Maharajan Sivasubramanian,1 Chia-Hui Chu,1 Yao-Chen Chuang,1,3 Yiu-Kay Lai,2 Leu-Wei Lo1 1Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan; 2Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; 3Department of...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2023-07-01
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| Series: | International Journal of Nanomedicine |
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| Online Access: | https://www.dovepress.com/a-dual-concentration-tailored-cytokine-chemo-nanosystem-to-alleviate-m-peer-reviewed-fulltext-article-IJN |
| _version_ | 1797769087330287616 |
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| author | Hsia Y Sivasubramanian M Chu CH Chuang YC Lai YK Lo LW |
| author_facet | Hsia Y Sivasubramanian M Chu CH Chuang YC Lai YK Lo LW |
| author_sort | Hsia Y |
| collection | DOAJ |
| description | Yu Hsia,1,2 Maharajan Sivasubramanian,1 Chia-Hui Chu,1 Yao-Chen Chuang,1,3 Yiu-Kay Lai,2 Leu-Wei Lo1 1Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan; 2Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; 3Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, TaiwanCorrespondence: Leu-Wei Lo, Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Zhunan, Taiwan, Tel +886-37-206-166 Ext 37115, Fax +886-37-586-440, Email lwlo@nhri.edu.tw Yiu-Kay Lai, Institute of Biotechnology, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, 300044, Taiwan, Tel +866-35-742-745, Email lslyk@life.nthu.edu.twBackground: Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR.Methods: We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR.Results: The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox.Conclusion: We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.Graphical Abstract: Keywords: cytokine cancer therapy, tumor necrosis factor alpha, mesoporous silica nanoparticle, pH-responsive controlled release, intrinsic/extrinsic apoptosis pathways, cancer multidrug resistance |
| first_indexed | 2024-03-12T21:03:48Z |
| format | Article |
| id | doaj.art-385a98cdb85048f185a7b76ac1d1922a |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-03-12T21:03:48Z |
| publishDate | 2023-07-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-385a98cdb85048f185a7b76ac1d1922a2023-07-30T19:00:26ZengDove Medical PressInternational Journal of Nanomedicine1178-20132023-07-01Volume 184253427485528A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and ApoptosisHsia YSivasubramanian MChu CHChuang YCLai YKLo LWYu Hsia,1,2 Maharajan Sivasubramanian,1 Chia-Hui Chu,1 Yao-Chen Chuang,1,3 Yiu-Kay Lai,2 Leu-Wei Lo1 1Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan; 2Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; 3Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, TaiwanCorrespondence: Leu-Wei Lo, Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Zhunan, Taiwan, Tel +886-37-206-166 Ext 37115, Fax +886-37-586-440, Email lwlo@nhri.edu.tw Yiu-Kay Lai, Institute of Biotechnology, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, 300044, Taiwan, Tel +866-35-742-745, Email lslyk@life.nthu.edu.twBackground: Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR.Methods: We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR.Results: The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox.Conclusion: We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.Graphical Abstract: Keywords: cytokine cancer therapy, tumor necrosis factor alpha, mesoporous silica nanoparticle, pH-responsive controlled release, intrinsic/extrinsic apoptosis pathways, cancer multidrug resistancehttps://www.dovepress.com/a-dual-concentration-tailored-cytokine-chemo-nanosystem-to-alleviate-m-peer-reviewed-fulltext-article-IJNcytokine cancer therapytumor necrosis factor alphamesoporous silica nanoparticleph-responsive controlled releaseintrinsic/extrinsic apoptosis pathwayscancer multidrug resistance |
| spellingShingle | Hsia Y Sivasubramanian M Chu CH Chuang YC Lai YK Lo LW A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis International Journal of Nanomedicine cytokine cancer therapy tumor necrosis factor alpha mesoporous silica nanoparticle ph-responsive controlled release intrinsic/extrinsic apoptosis pathways cancer multidrug resistance |
| title | A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis |
| title_full | A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis |
| title_fullStr | A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis |
| title_full_unstemmed | A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis |
| title_short | A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis |
| title_sort | dual concentration tailored cytokine chemo nanosystem to alleviate multidrug resistance and redirect balance of cancer proliferation and apoptosis |
| topic | cytokine cancer therapy tumor necrosis factor alpha mesoporous silica nanoparticle ph-responsive controlled release intrinsic/extrinsic apoptosis pathways cancer multidrug resistance |
| url | https://www.dovepress.com/a-dual-concentration-tailored-cytokine-chemo-nanosystem-to-alleviate-m-peer-reviewed-fulltext-article-IJN |
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