Original articles
Congcong Lin, Fan Tong, Rui Liu, Rou Xie, Ting Lei, Yuxiu Chen, Zhihang Yang, Huile Gao, Xiangrong Yu. GSH-responsive SN38 dimer-loaded shapetransformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy[J]. Acta Pharmaceutica Sinica B, 2020, 10(12): 2348-2361

GSH-responsive SN38 dimer-loaded shapetransformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy
Congcong Lina,b, Fan Tongc, Rui Liuc, Rou Xiec, Ting Leic, Yuxiu Chenc, Zhihang Yangc, Huile Gaoc, Xiangrong Yua
a Department of Radiology, Zhuhai People's Hospital, Jinan University, Zhuhai 519000, China;
b Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China;
c Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Sichuan 610041, China
Abstract:
Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92±1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.
Key words:    Shape-transformable    SN38 dimer    GSH-responsive    Chemo-photodynamic therapy    iRGD    Co-administration    Ce6    Breast cancer   
Received: 2020-07-26     Revised: 2020-09-12
DOI: 10.1016/j.apsb.2020.10.009
Funds: The authors gratefully acknowledge the financial support from National Natural Science Foundation of China (Nos. 81961138009; 82071915), Research Funds of Sichuan Science and Technology Department (No.19YYJC2250, China), 111 Project (No. B18035, China), Fundamental Research Funds for the Central Universities, and Natural Science Foundation of Heilongjiang Province of China (No. YQ2019H004).
Corresponding author: Huile Gao, gaohuile@scu.edu.cn;Xiangrong Yu, yxr00125040@126.com     Email:gaohuile@scu.edu.cn;yxr00125040@126.com
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Congcong Lin
Fan Tong
Rui Liu
Rou Xie
Ting Lei
Yuxiu Chen
Zhihang Yang
Huile Gao
Xiangrong Yu

References:
1. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine:progress, challenges and opportunities. Nat Rev Cancer 2017;17:20-37.
2. Danhier F. To exploit the tumor microenvironment:since the EPR effect fails in the clinic, what is the future of nanomedicine?. J Control Release 2016;244:108-21.
3. Perry JL, Reuter KG, Luft JC, Pecot CV, Zamboni W, DeSimone JM. Mediating passive tumor accumulation through particle size, tumor type, and location. Nano Lett 2017;17:2879-86.
4. Li C, Wang JC, Wang YG, Gao HL, Wei G, Huang YZ, et al. Recent progress in drug delivery. Acta Pharm Sin B 2019;9:1145-62.
5. Sykes EA, Chen J, Zheng G, Chan WC. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 2014;8:5696-706.
6. Hickey JW, Santos JL, Williford JM, Mao HQ. Control of polymeric nanoparticle size to improve therapeutic delivery. J Control Release 2015;219:536-47.
7. Shao D, Lu MM, Zhao YW, Zhang F, Tan YF, Zheng X, et al. The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution. Acta Biomater 2017;49:531-40.
8. Yu WQ, Shevtsov M, Chen XC, Gao HL. Advances in aggregatable nanoparticles for tumor-targeted drug delivery. Chin Chem Lett 2020; 31:1366-74.
9. Tang L, Yang XJ, Yin Q, Cai KM, Wang H, Chaudhury I, et al. Investigating the optimal size of anticancer nanomedicine. Proc Natl Acad Sci U S A 2014;111:15344-9.
10. Kibria G, Hatakeyama H, Ohga N, Hida K, Harashima H. The effect of liposomal size on the targeted delivery of doxorubicin to Integrin avb3-expressing tumor endothelial cells. Biomaterials 2013;34:5617-27.
11. Hu C, Cun XL, Ruan SB, Liu R, Xiao W, Yang XT, et al. Enzymetriggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy. Biomaterials 2018; 168:64-75.
12. Ruan SB, He Q, Gao HL. Matrix metalloproteinase triggered sizeshrinkable gelatin-gold fabricated nanoparticles for tumor microenvironment sensitive penetration and diagnosis of glioma. Nanoscale 2015;7:9487-96.
13. Ruan S, Cao X, Cun XL, Hu GL, Zhou Y, Zhang YJ, et al. Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release. Biomaterials 2015;60:100-10.
14. Yu WQ, Liu R, Zhou Y, Gao HL. Size-tunable strategies for a tumor targeted drug delivery system. ACS Cent Sci 2020;6:100-16.
15. Zhong L, Xu L, Liu YY, Li QS, Zhao DY, Li ZB, et al. Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy. Acta Pharm Sin B 2019;9:397-409.
16. Hu XX, He PP, Qi GB, Gao YJ, Lin YX, Yang C, et al. Transformable nanomaterials as an artificial extracellular matrix for inhibiting tumor invasion and metastasis. ACS Nano 2017;11:4086-96.
17. Bellat V, Ting R, Southard TL, Vahdat L, Molina H, Fernandez J, et al. Functional peptide nanofibers with unique tumor targeting and enzyme-induced local retention properties. Adv Funct Mater 2018;28:1803969.
18. Liu R, Yu MN, Yang XT, Umeshappa CS, Hu C, Yu WQ, et al. Linear chimeric triblock molecules self-assembled micelles with controllably transformable property to enhance tumor retention for chemo-photodynamic therapy of breast cancer. Adv Funct Mater 2019;29:1808462.
19. Wang Y, Wei GY, Zhang XB, Xu FN, Xiong X, Zhou SB. A step-bystep multiple stimuli-responsive nanoplatform for enhancing combined chemo-photodynamic therapy. Adv Mater 2017;29:201605357.
20. Lee Y, Lee S, Lee DY, Yu B, Miao W, Jon S. Multistimuli-responsive bilirubin nanoparticles for anticancer therapy. Angew Chem Int Ed Engl 2016;55:10676-80.
21. Qian CG, Yu JC, Chen YL, Hu QY, Xiao XZ, Sun WJ, et al. Lightactivated hypoxia-responsive nanocarriers for enhanced anticancer therapy. Adv Mater 2016;28:3313-20.
22. Anchordoquy TJ, Barenholz Y, Boraschi D, Chorny M, Decuzzi P, Dobrovolskaia MA, et al. Mechanisms and barriers in cancer nanomedicine:addressing challenges, looking for solutions. ACS Nano 2017;11:12-8.
23. Liu R, An Y, Jia WF, Wang YS, Wu Y, Zhen YH, et al. Macrophagemimic shape changeable nanomedicine retained in tumor for multimodal therapy of breast cancer. J Control Release 2020;321:589-601.
24. Yu WQ, He XQ, Yang ZH, Yang XT, Xiao W, Liu R, et al. Sequentially responsive biomimetic nanoparticles with optimal size in combination with checkpoint blockade for cascade synergetic treatment of breast cancer and lung metastasis. Biomaterials 2019;217:119309.
25. Yang L, Gao P, Huang Y, Lu X, Chang Q, Pan W, et al. Boosting the photodynamic therapy efficiency with a mitochondria-targeted nanophotosensitizer. Chin Chem Lett 2019;30:1293-6.
26. Jiang Q, Liu Y, Guo RR, Yao XX, Yang W. Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors. Biomaterials 2018;192:292-308.
27. Pei Q, Hu XL, Zheng XH, Liu S, Li Y, Jing XB, et al. Light-activatable red blood cell membrane-camouflaged dimeric prodrug nanoparticles for synergistic photodynamic/chemotherapy. ACS Nano 2018;12:1630-41.
28. He X, Cai KM, Zhang Y, Lu YF, Guo Q, Zhang YJ, et al. Dimeric prodrug self-delivery nanoparticles with enhanced drug loading and bioreduction responsiveness for targeted cancer therapy. ACS Appl Mater Interfaces 2018;10:39455-67.
29. Song Y, Li D, He JL, Zhang MZ, Ni PH. Facile preparation of pHresponsive PEGylated prodrugs for activated intracellular drug delivery. Chin Chem Lett 2019;30:2027-31.
30. Zheng P, Liu Y, Chen JJ, Xu WG, Li G, Ding JX. Targeted pHresponsive polyion complex micelle for controlled intracellular drug delivery. Chin Chem Lett 2020;31:1178-82.
31. Yang X, Hu C, Tong F, Liu R, Zhou Y, Qin L, et al. Tumor microenvironment-responsive dual drug dimer-loaded pegylated bilirubin nanoparticles for improved drug delivery and enhanced immunechemotherapy of breast cancer. Adv Funct Mater 2019;29:1901896.
32. Wang HX, Chen JM, Xu C, Shi LL, Tayier M, Zhou JH, et al. Cancer nanomedicines stabilized by p-p stacking between heterodimeric prodrugs enable exceptionally high drug loading capacity and safer delivery of drug combinations. Theranostics 2017;7:3638.
33. Bala V, Rao S, Boyd BJ, Prestidge CA. Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38. J Control Release 2013;172:48-61.
34. Guo Q, Luo P, Luo Y, Du F, Lu W, Liu SY, et al. Fabrication of biodegradable micelles with sheddable poly(ethylene glycol) shells as the carrier of 7-ethyl-10-hydroxy-camptothecin. Colloids Surf B Biointerfaces 2012;100:138-45.
35. Fujiwara Y, Minami H. An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 2010;11:391-406.
36. Takakura A, Kurita A, Asahara T, Yokoba M, Yamamoto M, Ryuge S, et al. Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat. Oncol Lett 2012;3:520-4.
37. Wang CC, Liu LC, Cao HL, Zhang WA. Intracellular GSH-activated galactoside photosensitizers for targeted photodynamic therapy and chemotherapy. Biomater Sci 2017;5:274-84.
38. Such GK, Yan Y, Johnston AP, Gunawan ST, Caruso F. Interfacing materials science and biology for drug carrier design. Adv Mater 2015; 27:2278-97.
39. Ruan SB, Xiao W, Hu C, Zhang HJ, Rao JD, Wang SH, et al. Ligandmediated and enzyme-directed precise targeting and retention for the enhanced treatment of glioblastoma. ACS Appl Mater Interfaces 2017; 9:20348-60.
40. Hu C, Yang XT, Liu R, Ruan SB, Zhou Y, Xiao W, et al. Coadministration of iRGD with multistage responsive nanoparticles enhanced tumor targeting and penetration abilities for breast cancer Therapy. ACS Appl Mater Interfaces 2018;10:22571-9.
41. Desgrosellier JS, Cheresh DA. Integrins in cancer:biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10:9-22.
42. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A 2009;106:16157-62.
43. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 2010;328:1031-5.
44. Liu R, Xiao W, Hu C, Xie R, Gao HL. Theranostic size-reducible and no donor conjugated gold nanocluster fabricated hyaluronic acid nanoparticle with optimal size for combinational treatment of breast cancer and lung metastasis. J Control Release 2018;278:127-39.
45. Zhang X, Lin CC, Lu AP, Lin G, Chen HJ, Liu Q, et al. Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma. Drug Deliv 2017;24:986-98.
46. Lin CC, Zhang X, Chen HB, Bian ZX, Zhang G, Riaz MK, et al. Dualligand modified liposomes provide effective local targeted delivery of lung-cancer drug by antibody and tumor lineage-homing cell-penetrating peptide. Drug Deliv 2018;25:256-66.
47. Chereddy KK, Her C-H, Comune M, Moia C, Lopes A, Porporato PE, et al. PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing. J Control Release 2014;194:138-47.
48. Cun XL, Chen JT, Ruan SB, Zhang L, Wan JY, He Q, et al. A novel strategy through combining iRGD peptide with tumormicroenvironment-responsive and multistage nanoparticles for deep tumor penetration. ACS Appl Mater Interfaces 2015;7:27458-66.
49. Guo Y, Jiang K, Shen ZC, Zheng GR, Fan LL, Zhao RR, et al. A small molecule nanodrug by self-assembly of dual anticancer drugs and photosensitizer for synergistic near-infrared cancer theranostics. ACS Appl Mater Interfaces 2017;9:43508-19.
50. Khodadadei F, Safarian S, Ghanbari N. Methotrexate-loaded nitrogendoped graphene quantum dots nanocarriers as an efficient anticancer drug delivery system. Mater Sci Eng C Mater Biol Appl 2017;79:280-5.
51. Mo R, Gu Z. Tumor microenvironment and intracellular signalactivated nanomaterials for anticancer drug delivery. Mater Today 2016;19:274-83.
52. Cai KM, He X, Song ZY, Yin Q, Zhang YF, Uckun FM, et al. Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency. J Am Chem Soc 2015;137:3458-61.
53. Danhier F, Feron O, Pre át V. To exploit the tumor microenvironment:passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 2010;148:135-46.
54. Pang HB, Braun GB, She ZG, Kotamraju VR, Sugahara KN, Teesalu T, et al. A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity. J Control Release 2014;175:48-53.
55. Yang YY, Chen QL, Li SY, Ma W, Yao GY, Ren F, et al. iRGDmediated and enzyme-induced precise targeting and retention of gold nanoparticles for the enhanced imaging and treatment of breast cancer. J Biomed Nanotechnol 2018;14:1396-408.
56. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine:progress, challenges and opportunities. Nat Rev Cancer 2017;17:20.
57. Cho HJ, Lee SJ, Park SJ, Paik CH, Lee SM, Kim S, et al. Activatable iRGD-based peptide monolith:targeting, internalization, and fluorescence activation for precise tumor imaging. J Control Release 2016; 237:177-84.
58. Ruoslahti E. Peptides as targeting elements and tissue penetration devices for nanoparticles. Adv Mater 2012;24:3747-56.
59. Sugahara KN, Braun GB, de Mendoza TH, Kotamraju VR, French RP, Lowy AM, et al. Tumor-penetrating iRGD peptide inhibits metastasis. Mol Cancer Ther 2015;14:120-8.
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