A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer
BackgroundModifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an o...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:d6509ccdcb114e9f89b72e83ca5fd3562021-11-10T08:12:24ZA Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer2234-943X10.3389/fonc.2021.737323https://doaj.org/article/d6509ccdcb114e9f89b72e83ca5fd3562021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.737323/fullhttps://doaj.org/toc/2234-943XBackgroundModifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.MethodsWe developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.ResultsPPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4+ and CD8+ T cells was found in tumors from PPA1-DOX treated mice.ConclusionsWe describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.Maolin WangMaolin WangXing-sheng ShuMeiqi LiYilin ZhangYouli YaoXiaoyan HuangJianna LiPengfei WeiZhendan HeJun LuJun LuYing YingFrontiers Media S.A.articletarget delivery systemcolon cancerPD-L1 targeting polypeptidepH sensitive linkerchemotherapeutics drug releaseNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021) |
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DOAJ |
| language |
EN |
| topic |
target delivery system colon cancer PD-L1 targeting polypeptide pH sensitive linker chemotherapeutics drug release Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
target delivery system colon cancer PD-L1 targeting polypeptide pH sensitive linker chemotherapeutics drug release Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Maolin Wang Maolin Wang Xing-sheng Shu Meiqi Li Yilin Zhang Youli Yao Xiaoyan Huang Jianna Li Pengfei Wei Zhendan He Jun Lu Jun Lu Ying Ying A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| description |
BackgroundModifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.MethodsWe developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.ResultsPPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4+ and CD8+ T cells was found in tumors from PPA1-DOX treated mice.ConclusionsWe describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity. |
| format |
article |
| author |
Maolin Wang Maolin Wang Xing-sheng Shu Meiqi Li Yilin Zhang Youli Yao Xiaoyan Huang Jianna Li Pengfei Wei Zhendan He Jun Lu Jun Lu Ying Ying |
| author_facet |
Maolin Wang Maolin Wang Xing-sheng Shu Meiqi Li Yilin Zhang Youli Yao Xiaoyan Huang Jianna Li Pengfei Wei Zhendan He Jun Lu Jun Lu Ying Ying |
| author_sort |
Maolin Wang |
| title |
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| title_short |
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| title_full |
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| title_fullStr |
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| title_full_unstemmed |
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer |
| title_sort |
novel strategy conjugating pd-l1 polypeptide with doxorubicin alleviates chemotherapeutic resistance and enhances immune response in colon cancer |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/d6509ccdcb114e9f89b72e83ca5fd356 |
| work_keys_str_mv |
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