Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing
Engineered mesenchymal stem cells (MSCs) have been investigated extensively for gene delivery and, more recently, for targeted small molecule delivery. While preclinical studies demonstrate the potential of MSCs for targeted delivery, clinical studies suggest that tumor homing of native MSCs may be...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-04-01
|
| Series: | Materials Today Bio |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006423000273 |
| _version_ | 1827975091147767808 |
|---|---|
| author | Swayam Prabha Carmen Merali Drishti Sehgal Emmanuelle Nicolas Nitu Bhaskar Magda Flores Shubhmita Bhatnagar Susheel Kumar Nethi Carlos A. Barrero Salim Merali Jayanth Panyam |
| author_facet | Swayam Prabha Carmen Merali Drishti Sehgal Emmanuelle Nicolas Nitu Bhaskar Magda Flores Shubhmita Bhatnagar Susheel Kumar Nethi Carlos A. Barrero Salim Merali Jayanth Panyam |
| author_sort | Swayam Prabha |
| collection | DOAJ |
| description | Engineered mesenchymal stem cells (MSCs) have been investigated extensively for gene delivery and, more recently, for targeted small molecule delivery. While preclinical studies demonstrate the potential of MSCs for targeted delivery, clinical studies suggest that tumor homing of native MSCs may be inefficient. We report here a surprising finding that loading MSCs with the anticancer drug paclitaxel (PTX) by nanoengineering results in significantly improved tumor homing compared to naïve MSCs. Loading PTX in MSCs results in increased levels of mitochondrial reactive oxygen species (ROS). In response to this oxidative stress, MSCs upregulate two important set of proteins. First were critical antioxidant proteins, most importantly nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of antioxidant responses; upregulation of antioxidant proteins may explain how MSCs protect themselves from drug-induced oxidative stress. The second was CXCR4, a direct target of Nrf2 and a key mediator of tumor homing; upregulation of CXCR4 suggested a mechanism that may underlie the improved tumor homing of nanoengineered MSCs. In addition to demonstrating the potential mechanism of improved tumor targeting of nanoengineered MSCs, our studies reveal that MSCs utilize a novel mechanism of resistance against drug-induced oxidative stress and cell death, explaining how MSCs can deliver therapeutic concentrations of cytotoxic payload while maintaining their viability. |
| first_indexed | 2024-04-09T20:04:54Z |
| format | Article |
| id | doaj.art-fd99184c8f4c45d48e754b40cbaaca3f |
| institution | Directory Open Access Journal |
| issn | 2590-0064 |
| language | English |
| last_indexed | 2024-04-09T20:04:54Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj.art-fd99184c8f4c45d48e754b40cbaaca3f2023-04-02T06:14:36ZengElsevierMaterials Today Bio2590-00642023-04-0119100567Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homingSwayam Prabha0Carmen Merali1Drishti Sehgal2Emmanuelle Nicolas3Nitu Bhaskar4Magda Flores5Shubhmita Bhatnagar6Susheel Kumar Nethi7Carlos A. Barrero8Salim Merali9Jayanth Panyam10Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA; Cancer Signaling and Tumor Microenvironment Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA, 19111, USA; Corresponding author. Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.School of Pharmacy, Temple University, Philadelphia, PA, 19140, USAFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USACancer Signaling and Tumor Microenvironment Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA, 19111, USASchool of Pharmacy, Temple University, Philadelphia, PA, 19140, USASchool of Pharmacy, Temple University, Philadelphia, PA, 19140, USASchool of Pharmacy, Temple University, Philadelphia, PA, 19140, USAFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USASchool of Pharmacy, Temple University, Philadelphia, PA, 19140, USASchool of Pharmacy, Temple University, Philadelphia, PA, 19140, USACancer Signaling and Tumor Microenvironment Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA, 19111, USA; School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA; Corresponding author. School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA.Engineered mesenchymal stem cells (MSCs) have been investigated extensively for gene delivery and, more recently, for targeted small molecule delivery. While preclinical studies demonstrate the potential of MSCs for targeted delivery, clinical studies suggest that tumor homing of native MSCs may be inefficient. We report here a surprising finding that loading MSCs with the anticancer drug paclitaxel (PTX) by nanoengineering results in significantly improved tumor homing compared to naïve MSCs. Loading PTX in MSCs results in increased levels of mitochondrial reactive oxygen species (ROS). In response to this oxidative stress, MSCs upregulate two important set of proteins. First were critical antioxidant proteins, most importantly nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of antioxidant responses; upregulation of antioxidant proteins may explain how MSCs protect themselves from drug-induced oxidative stress. The second was CXCR4, a direct target of Nrf2 and a key mediator of tumor homing; upregulation of CXCR4 suggested a mechanism that may underlie the improved tumor homing of nanoengineered MSCs. In addition to demonstrating the potential mechanism of improved tumor targeting of nanoengineered MSCs, our studies reveal that MSCs utilize a novel mechanism of resistance against drug-induced oxidative stress and cell death, explaining how MSCs can deliver therapeutic concentrations of cytotoxic payload while maintaining their viability.http://www.sciencedirect.com/science/article/pii/S2590006423000273Mesenchymal stem cellsTumor homingNanoengineeringTargeted drug deliveryDrug resistanceOxidative stress |
| spellingShingle | Swayam Prabha Carmen Merali Drishti Sehgal Emmanuelle Nicolas Nitu Bhaskar Magda Flores Shubhmita Bhatnagar Susheel Kumar Nethi Carlos A. Barrero Salim Merali Jayanth Panyam Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing Materials Today Bio Mesenchymal stem cells Tumor homing Nanoengineering Targeted drug delivery Drug resistance Oxidative stress |
| title | Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing |
| title_full | Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing |
| title_fullStr | Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing |
| title_full_unstemmed | Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing |
| title_short | Incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response, CXCR4 expression and enhances tumor homing |
| title_sort | incorporation of paclitaxel in mesenchymal stem cells using nanoengineering upregulates antioxidant response cxcr4 expression and enhances tumor homing |
| topic | Mesenchymal stem cells Tumor homing Nanoengineering Targeted drug delivery Drug resistance Oxidative stress |
| url | http://www.sciencedirect.com/science/article/pii/S2590006423000273 |
| work_keys_str_mv | AT swayamprabha incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT carmenmerali incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT drishtisehgal incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT emmanuellenicolas incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT nitubhaskar incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT magdaflores incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT shubhmitabhatnagar incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT susheelkumarnethi incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT carlosabarrero incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT salimmerali incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming AT jayanthpanyam incorporationofpaclitaxelinmesenchymalstemcellsusingnanoengineeringupregulatesantioxidantresponsecxcr4expressionandenhancestumorhoming |