Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin
Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells....
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/1035 |
| _version_ | 1797513498699235328 |
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| author | Dominick Salerno Stavroula Sofou |
| author_facet | Dominick Salerno Stavroula Sofou |
| author_sort | Dominick Salerno |
| collection | DOAJ |
| description | Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles. |
| first_indexed | 2024-03-10T06:17:25Z |
| format | Article |
| id | doaj.art-9cfc1d8e973743bfb8955031c3eff484 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:17:25Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9cfc1d8e973743bfb8955031c3eff4842023-11-22T19:36:27ZengMDPI AGPharmaceuticals1424-82472021-10-011410103510.3390/ph14101035Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and CisplatinDominick Salerno0Stavroula Sofou1Chemical and Biomolecular Engineering (ChemBE), Institute for NanoBioTechnology (INBT), Baltimore, MD 21218, USAChemical and Biomolecular Engineering (ChemBE), Institute for NanoBioTechnology (INBT), Baltimore, MD 21218, USACombinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles.https://www.mdpi.com/1424-8247/14/10/1035doxorubicincisplatincombination chemotherapytumor spatiotemporal deliverytriple-negative breast cancerliposomes |
| spellingShingle | Dominick Salerno Stavroula Sofou Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin Pharmaceuticals doxorubicin cisplatin combination chemotherapy tumor spatiotemporal delivery triple-negative breast cancer liposomes |
| title | Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin |
| title_full | Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin |
| title_fullStr | Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin |
| title_full_unstemmed | Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin |
| title_short | Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin |
| title_sort | growth inhibition of triple negative breast cancer the role of spatiotemporal delivery of neoadjuvant doxorubicin and cisplatin |
| topic | doxorubicin cisplatin combination chemotherapy tumor spatiotemporal delivery triple-negative breast cancer liposomes |
| url | https://www.mdpi.com/1424-8247/14/10/1035 |
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