Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy
Abstract Background Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-022-01383-z |
| _version_ | 1798041663683166208 |
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| author | Ting Zhao Ce Liang Yanrong Zhao Xiangdong Xue Zhao Ma Jinlong Qi Haitao Shen Shaokun Yang Jia Zhang Qingzhong Jia Qing Du Deying Cao Bai Xiang Hailin Zhang Xianrong Qi |
| author_facet | Ting Zhao Ce Liang Yanrong Zhao Xiangdong Xue Zhao Ma Jinlong Qi Haitao Shen Shaokun Yang Jia Zhang Qingzhong Jia Qing Du Deying Cao Bai Xiang Hailin Zhang Xianrong Qi |
| author_sort | Ting Zhao |
| collection | DOAJ |
| description | Abstract Background Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. Results In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. Conclusion These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment. Graphical Abstract |
| first_indexed | 2024-04-11T22:24:41Z |
| format | Article |
| id | doaj.art-6f0fabf9ddca49a6ab9cb87a2079c823 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-11T22:24:41Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-6f0fabf9ddca49a6ab9cb87a2079c8232022-12-22T03:59:50ZengBMCJournal of Nanobiotechnology1477-31552022-04-0120112310.1186/s12951-022-01383-zMultistage pH-responsive codelivery liposomal platform for synergistic cancer therapyTing Zhao0Ce Liang1Yanrong Zhao2Xiangdong Xue3Zhao Ma4Jinlong Qi5Haitao Shen6Shaokun Yang7Jia Zhang8Qingzhong Jia9Qing Du10Deying Cao11Bai Xiang12Hailin Zhang13Xianrong Qi14Key Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityDepartment of Pharmacology, Hebei Medical UniversityDepartment of Hematology, Hebei Children’s Hospital, Hebei Medical UniversitySchool of Pharmaceutical Science, Shanghai Jiao Tong UniversityDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Pharmacology, Hebei Medical UniversityLaboratory of Pathology, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityKey Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical UniversityDepartment of Pharmacology, Hebei Medical UniversitySchool of Pharmaceutical Sciences, Peking UniversityAbstract Background Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. Results In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. Conclusion These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment. Graphical Abstracthttps://doi.org/10.1186/s12951-022-01383-zCancer therapypH-responsiveLiposomeSmall interfering RNADocetaxelCo-delivery system |
| spellingShingle | Ting Zhao Ce Liang Yanrong Zhao Xiangdong Xue Zhao Ma Jinlong Qi Haitao Shen Shaokun Yang Jia Zhang Qingzhong Jia Qing Du Deying Cao Bai Xiang Hailin Zhang Xianrong Qi Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy Journal of Nanobiotechnology Cancer therapy pH-responsive Liposome Small interfering RNA Docetaxel Co-delivery system |
| title | Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy |
| title_full | Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy |
| title_fullStr | Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy |
| title_full_unstemmed | Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy |
| title_short | Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy |
| title_sort | multistage ph responsive codelivery liposomal platform for synergistic cancer therapy |
| topic | Cancer therapy pH-responsive Liposome Small interfering RNA Docetaxel Co-delivery system |
| url | https://doi.org/10.1186/s12951-022-01383-z |
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