PURPOSE: Due to the shortcomings of nanocarriers, the development of carrier-free nanodelivery systems has attracted more and more attention in cancer treatment. However, there are few studies on carrier-free nanosystems that can simultaneously achieve monitoring functions. Here a multifunctional carrier-free nanosystem loaded with curcumin and irinotecan hydrochloride was established for the treatment and monitoring of gastric cancer. METHODS: In this study, an irinotecan hydrochloride-curcumin nanosystem in the early stage (the system is named SICN) was prepared. Based on the fluorescence of curcumin, flow cytometry, laser confocal microscopy, and zebrafish fluorescence imaging were used to study the monitoring function of SICN in vivo and in vitro. In addition, HGC-27 human gastric cancer cells were used to study SICN cytotoxicity. RESULTS: Flow cytometry and zebrafish fluorescence imaging monitoring results showed that the uptake of SICN was significantly higher than free curcumin, and the excretion rate was lower. SICN had higher accumulation and retention in cells and zebrafish. Laser confocal microscopy monitoring results showed that SICN was internalized into HGC-27 cells through multiple pathways, including macropinocytosis, caveolin, and clathrin-mediated and clathrin -independent endocytosis, and distributed intracellularly throughout the whole cytoplasm, including lysosomes and Golgi apparatus. In vitro cell experiments showed that SICN nanoparticles were more toxic than single components, and HGC-27 cells had more absorption and higher toxicity to nanoparticles under slightly acidic conditions. CONCLUSION: SICN is a promising carrier-free nanoparticle, and the combination of two single-component therapies can exert a synergistic antitumor effect. When exposed to a tumor acidic environment, SICN showed stronger cytotoxicity due to charge conversion. More importantly, the nanoparticles' self-monitoring function has been developed, opening up new ideas for combined tumor therapy.

Centre of Polymer Systems Tomas Bata University in Zlin Zlin 76001 Czech Republic

Quantitative and Systems Biology Program University of California Merced CA 95343 USA

School of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu 611137 People's Republic of China

State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China Chengdu 611137 People's Republic of China

See more in PubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. doi:10.3322/caac.21590 PubMed DOI

Balakumar P, Maung UK, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res. 2016;113:600–609. doi:10.1016/j.phrs.2016.09.040 PubMed DOI

Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–289. doi:10.3322/caac.21349 PubMed DOI

Wang N, Zhou Y, Xu Y, et al. Molecular engineering of anti-PD-L1 peptide and photosensitizer for immune checkpoint blockade photodynamic-immunotherapy. Chem Eng J. 2020;400:125995. doi:10.1016/j.cej.2020.125995 DOI

Keall P, Nguyen DT, O’Brien R, et al. Real-time image guided ablative prostate cancer radiation therapy: results from the TROG 15.01 SPARK Trial. Int J Radiat Oncol Biol Phys. 2020;107(3):530–538. doi:10.1016/j.ijrobp.2020.03.014 PubMed DOI

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–2394. doi:10.1056/NEJMoa1214886 PubMed DOI

Van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378:230–240. doi:10.1056/NEJMoa1708618 PubMed DOI

Bertrand N, Wu J, Xu X, et al. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2–25. doi:10.1016/j.addr.2013.11.009 PubMed DOI PMC

Pham DT, Chokamonsirikun A, Phattaravorakarn V, et al. Polymeric micelles for pulmonary drug delivery: a comprehensive review. J Mater Sci. 2020;56:2016–2036. doi:10.1007/s10853-020-05361-4 DOI

Mirzaie Z, Barati M, Tokmedash MA. Anticancer drug delivery systems based on curcumin nanostructures: a review. Pharm Chem J. 2020;54(4):353–360. doi:10.1007/s11094-020-02203-0 DOI

Cai AY, Zhu YJ, Qi C. Biodegradable inorganic nanostructured biomaterials for drug delivery. Adv Mater Interfaces. 2020;7(20):1–30. doi:10.1002/admi.202000819 DOI

Perez-Herrero E, Fernandez-Medarde A. Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52–79. doi:10.1016/j.ejpb.2015.03.018 PubMed DOI

Zhou Q, Shao S, Wang J, et al. Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy. Nat Nanotechnol. 2019;14(8):799–809. doi:10.1038/s41565-019-0485-z PubMed DOI

Zhang J, Liang Y, Lin X, et al. Self-monitoring and self-delivery of photosensitizer-doped nanoparticles for highly effective combination cancer therapy in vitro and in vivo. ACS Nano. 2015;9(10):9741–9756. doi:10.1021/acsnano.5b02513 PubMed DOI

Kanamala M, Wilson WR, Yang M, et al. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review. Biomaterials. 2016;85:152–167. doi:10.1016/j.biomaterials.2016.01.061 PubMed DOI

Jia X, Zhang Y, Zou Y, et al. Dual intratumoral redox/enzyme-responsive NO-releasing nanomedicine for the specific, high-efficacy, and low-toxic cancer therapy. Adv Mater. 2018;30:1–9. doi:10.1002/adma.201704490 PubMed DOI

Zhang Y, Hu H, Tang W, et al. A multifunctional magnetic nanosystem based on “two strikes” effect for synergistic anticancer therapy in triple-negative breast cancer. J Control Release. 2020;322:401–415. doi:10.1016/j.jconrel.2020.03.036 PubMed DOI

Zhang Y, Yan J, Avellan A, et al. Temperature and pH responsive star polymers as nano-carriers with potential for in vivo agrochemical delivery. ACS Nano. 2020. doi:10.1021/acsnano.0c03140 PubMed DOI

Unnikrishnan BS, Maya S, Preethi GU, et al. Self-assembled drug loaded glycosyl-protein metal nanoconstruct: detailed synthetic procedure and therapeutic effect in solid tumor treatment. Colloids Surf B Biointerfaces. 2020;193. doi:10.1016/j.colsurfb.2020.111082 PubMed DOI

Zhang ZT, Wang RY, Huang XX, et al. Self-delivered and self-monitored chemo-photodynamic nanoparticles with light-triggered synergistic antitumor therapies by downregulation of HIF-1 alpha and Depletion of GSH. ACS Appl Mater Interfaces. 2020;12(5):5680–5694. doi:10.1021/acsami.9b23325 PubMed DOI

Parisi OI, Ruffo M, Malivindi R, et al. Molecularly imprinted polymers (MIPs) as theranostic systems for sunitinib controlled release and self-monitoring in cancer therapy. Pharmaceutics. 2020;12(1):1–18. doi:10.3390/pharmaceutics12010041 PubMed DOI PMC

Zhang H, Fan T, Chen W, et al. Recent advances of two-dimensional materials in smart drug delivery nano-systems. Bioact Mater. 2020;5(4):1071–1086. doi:10.1016/j.bioactmat.2020.06.012 PubMed DOI PMC

Xiao H, Guo Y, Liu H, et al. Structure-based design of charge-conversional drug self-delivery systems for better targeted cancer therapy. Biomaterials. 2020;232. doi:10.1016/j.biomaterials.2019.119701 PubMed DOI

Hassanzadeh K, Buccarello L, Dragotto J, et al. Obstacles against the marketing of curcumin as a drug. Int J Mol Sci. 2020;21(18):1–35. doi:10.3390/ijms21186619 PubMed DOI PMC

Scazzocchio B, Minghetti L, D’Archivio M. Interaction between gut microbiota and curcumin: a new key of understanding for the health effects of curcumin. Nutrients. 2020;12(9):1–18. doi:10.3390/nu12092499 PubMed DOI PMC

Westerfield M. The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio Rerio). 4th ed. Eugene: University of Oregon Press; 2000.

Fang J, Islam W, Maeda H. Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers. Adv Drug Deliv Rev. 2020;157:142–160. doi:10.1016/j.addr.2020.06.005 PubMed DOI

Chen K, Li X, Zhu H, et al. Endocytosis of nanoscale systems for cancer treatments. Curr Med Chem. 2018;25(25):3017–3035. doi:10.2174/0929867324666170428153056 PubMed DOI

Iversen T-G, Skotland T, Sandvig K. Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies. Nano Today. 2011;6(2):176–185. doi:10.1016/j.nantod.2011.02.003 DOI