Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice
Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil<sup>®</sup>, a formulation of DXR encapsulated in polyethylene gl...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/12/10/990 |
| _version_ | 1797550529855881216 |
|---|---|
| author | Takuma Takayama Taro Shimizu Amr S. Abu Lila Yuki Kanazawa Hidenori Ando Yu Ishima Tatsuhiro Ishida |
| author_facet | Takuma Takayama Taro Shimizu Amr S. Abu Lila Yuki Kanazawa Hidenori Ando Yu Ishima Tatsuhiro Ishida |
| author_sort | Takuma Takayama |
| collection | DOAJ |
| description | Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil<sup>®</sup>, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil<sup>®</sup> on host antitumor immunity is not well understood. In this study, Doxil<sup>®</sup> efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil<sup>®</sup>. In immunocompetent mice, Doxil<sup>®</sup> increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil<sup>®</sup>. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells. |
| first_indexed | 2024-03-10T15:30:38Z |
| format | Article |
| id | doaj.art-7a571134fa3349009f2d559d51bee2a0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T15:30:38Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-7a571134fa3349009f2d559d51bee2a02023-11-20T17:42:18ZengMDPI AGPharmaceutics1999-49232020-10-01121099010.3390/pharmaceutics12100990Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent MiceTakuma Takayama0Taro Shimizu1Amr S. Abu Lila2Yuki Kanazawa3Hidenori Ando4Yu Ishima5Tatsuhiro Ishida6Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDepartment of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptDepartment of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDepartment of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDepartment of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDepartment of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanDoxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil<sup>®</sup>, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil<sup>®</sup> on host antitumor immunity is not well understood. In this study, Doxil<sup>®</sup> efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil<sup>®</sup>. In immunocompetent mice, Doxil<sup>®</sup> increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil<sup>®</sup>. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.https://www.mdpi.com/1999-4923/12/10/990antitumor immunitychemotherapydoxorubicin (DXR)drug delivery systemDoxil<sup>®</sup> |
| spellingShingle | Takuma Takayama Taro Shimizu Amr S. Abu Lila Yuki Kanazawa Hidenori Ando Yu Ishima Tatsuhiro Ishida Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice Pharmaceutics antitumor immunity chemotherapy doxorubicin (DXR) drug delivery system Doxil<sup>®</sup> |
| title | Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice |
| title_full | Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice |
| title_fullStr | Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice |
| title_full_unstemmed | Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice |
| title_short | Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil<sup>®</sup>) in C26 Tumor-Bearing Immunocompetent Mice |
| title_sort | adjuvant antitumor immunity contributes to the overall antitumor effect of pegylated liposomal doxorubicin doxil sup r sup in c26 tumor bearing immunocompetent mice |
| topic | antitumor immunity chemotherapy doxorubicin (DXR) drug delivery system Doxil<sup>®</sup> |
| url | https://www.mdpi.com/1999-4923/12/10/990 |
| work_keys_str_mv | AT takumatakayama adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT taroshimizu adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT amrsabulila adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT yukikanazawa adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT hidenoriando adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT yuishima adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice AT tatsuhiroishida adjuvantantitumorimmunitycontributestotheoverallantitumoreffectofpegylatedliposomaldoxorubicindoxilsupsupinc26tumorbearingimmunocompetentmice |