Active targeted drug delivery system constructed from functionalized pillararenes for chemo/photodynamic synergistic therapy

Abstract

Nowadays, although functionalized pillararenes have been widely designed to be used in drug delivery system, targeted group modified pillararenes have been seldom reported and used in tumor multimodal therapy. Herein, a functionalized pillararene with a polyethylene glycol chain and triphenylphosphonium cation WP5-PEG-TPP was designed and synthesized. Subsequently, an active targeted drug delivery system was constructed based on its host-guest interactions with a newly designed porphyrin derivative, Py-Por. The experimental results demonstrated that this drug delivery system has exhibited excellent targeting ability against tumor cells, but interestingly it could not enter normal cells. After loading the hypoxia-activated prodrug tirapazamine, the prepared nanodrugs displayed high lethality to tumor cells due to their chemo/photodynamic synergistic therapy capability, but negligible toxicity to normal cells. Preliminary therapeutic mechanism study elucidated the synergistic therapy process.

Graphical abstract

Keywords

durg delivery system / active targeting / pillararene / chemo/photodynamic synergistic therapy.

References

[1] Siegel R L , Giaquinto A N , Jemal A . Cancer Statistics, 2024. A Cancer Journal for Clinicians, 2024, 74(1): 12–49

[2] Torchilin V P . Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nature Reviews. Drug Discovery, 2014, 13(11): 813–827

[3] LuZ RQiaoP. Drug delivery in cancer therapy, quo vadis? Molecular Pharmaceutics, 2018, 15(9): 3603–3616

[4] Park S M , Aalipour A , Vermesh O , Yu J H , Gambhir S S . Towards clinically translatable in vivo nanodiagnostics. Nature Reviews. Materials, 2017, 2(5): 17014

[5] Wang A Z , Langer R , Farokhzad O C . Nanoparticle delivery of cancer drugs. Annual Review of Medicine, 2012, 63(1): 185–198

[6] Gao P , Pan W , Li N , Tang B . Boosting cancer therapy with organelle-targeted nanomaterials. ACS Applied Materials & Interfaces, 2019, 11(30): 26529–26558

[7] Liew S S , Qin X , Zhou J , Li L , Huang W , Yao S Q . Smart design of nanomaterials for mitochondria-targeted nanotherapeutics. Angewandte Chemie International Edition, 2020, 60(5): 2232–2256

[8] Wang K , Xiang Y , Pan W , Wang H , Li N , Tang B . Dual-targeted photothermal agents for enhanced cancer therapy. Chemical Science, 2020, 11(31): 8055–8072

[9] Webber M J , Langer R . Drug delivery by supramolecular design. Chemical Society Reviews, 2017, 46(21): 6600–6620

[10] Li Z , Song N , Yang Y W . Stimuli-responsive drug-delivery systems based on supramolecular nanovalves. Matter, 2019, 1(2): 345–368

[11] Zhou J , Rao L , Yu G , Cook T R , Chen X , Huang F . Supramolecular cancer nanotheranostics. Chemical Society Reviews, 2021, 50(4): 2839–2891

[12] Kwon N , Kim H , Li X , Yoon J . Supramolecular agents for combination of photodynamic therapy and other treatments. Chemical Science (Cambridge), 2021, 12(21): 7248–7268

[13] Feng W , Jin M , Yang K , Pei Y , Pei Z . Supramolecular delivery systems based on pillararenes. Chemical Communications, 2018, 54(97): 13626–13640

[14] Ogoshi T , Kakuta T , Yamagishi T A . Applications of pillar[n]arene-based supramolecular assemblies. Angewandte Chemie International Edition, 2018, 58(8): 2197–2206

[15] Zhang H , Liu Z , Zhao Y . Pillararene-based self-assembled amphiphiles. Chemical Society Reviews, 2018, 47(14): 5491–5528

[16] Song N , Lou X Y , Ma L , Gao H , Yang Y W . Supramolecular nanotheranostics based on pillarenes. Theranostics, 2019, 9(11): 3075–3093

[17] Xiao T , Qi L , Zhong W , Lin C , Wang R , Wang L . Stimuli-responsive nanocarriers constructed from pillar[n]arene-based supra-amphiphiles. Materials Chemistry Frontiers, 2019, 3(10): 1973–1993

[18] Wang C , Li H , Dong J , Chen Y , Luan X , Li X , Du X . Pillararene-based supramolecular vesicles for stimuli-responsive drug delivery. Chemistry, 2022, 28(71): 202202050

[19] Yang Q , Xu W , Cheng M , Zhang S , Kovaleva E G , Liang F , Tian D , Liu J A , Abdelhameed R M , Cheng J , Li H . Controlled release of drug molecules by pillararene-modified nanosystems. Chemical Communications, 2022, 58(20): 3255–3269

[20] Li X , Shen M , Yang J , Liu L , Yang Y W . Pillararene-based stimuli-responsive supramolecular delivery systems for cancer therapy. Advanced Materials, 2024, 36(16): 2313317

[21] Yang K , Zhang Z , Du J , Li W , Pei Z . Host-guest interaction based supramolecular photodynamic therapy systems: a promising candidate in the battle against cancer. Chemical Communications, 2020, 56(44): 5865–5876

[22] Zhu H , Wang H , Shi B , Shangguan L , Tong W , Yu G , Mao Z , Huang F . Supramolecular peptide constructed by molecular lego allowing programmable self-assembly for photodynamic therapy. Nature Communications, 2019, 10(1): 2412

[23] Muhammed M A H , Cruz L K , Emwas A H , El-Zohry A M , Moosa B , Mohammed O F , Khashab N M . Pillar[5]arene-stabilized silver nanoclusters: extraordinary stability and luminescence enhancement induced by host-guest interactions. Angewandte Chemie International Edition, 2019, 58(44): 15665–15670

[24] Xu X , Jerca F A , Van Hecke K , Jerca V V , Hoogenboom R . High compression strength single network hydrogels with pillar[5]arene junction points. Materials Horizons, 2020, 7(2): 566–573

[25] Cai Y , Zhang Z , Ding Y , Hu L , Wang J , Chen T , Yao Y . Recent development of pillar[n]arene-based amphiphiles. Chinese Chemical Letters, 2021, 32(4): 1267–1279

[26] Mi Y , Ma J , Liang W , Xiao C , Wu W , Zhou D , Yao J , Sun W , Sun J , Gao G . . Guest-binding-induced interhetero hosts charge transfer crystallization: selective coloration of commonly used organic solvents. Journal of the American Chemical Society, 2021, 143(3): 1553–1561

[27] TangRYeYZhuSWangYLuBYaoY. Pillar[6]arenes: from preparation, host-guest property to self-assembly and applications. Chinese Chemical Letters, 2023, 34(107734

[28] Xia J , Wang J , Zhao Q , Lu B , Yao Y . Dual-responsive drug-delivery system based on peg-functionalized pillararenes containing disulfide and amido bonds for cancer theranostics. ChemBioChem, 2023, 24(21): 202300513

[29] Feng Y , Qi S , Yu X , Zhang X , Zhu H , Yu G . Supramolecular modulation of tumor microenvironment through pillar[5]arene-based host–guest recognition to synergize cancer immunotherapy. Journal of the American Chemical Society, 2023, 145(34): 18789–18799

[30] Lu B , Xia J , Huang Y , Yao Y . The design strategy for pillararene based active targeted drug delivery systems. Chemical Communications, 2023, 59(81): 12091–12099

[31] Li Q L , Sun Y , Ren L , Wang X , Wang C , Li L , Yang Y W , Yu X , Yu J . Supramolecular nanosystem based on pillararene-capped cus nanoparticles for targeted chemo-photothermal therapy. ACS Applied Materials & Interfaces, 2018, 10(35): 29314–29324

[32] Lan S , Liu Y , Shi K , Ma D . Acetal-functionalized pillar[5]arene: a pH-responsive and versatile nanomaterial for the delivery of chemotherapeutic agents. ACS Applied Bio Materials, 2020, 3(4): 2325–2333

[33] Cen M , Ding Y , Wang J , Yuan X , Lu B , Wang Y , Yao Y . Cationic water-soluble pillar[5]arene-modified Cu_2–xSe nanoparticles: supramolecular trap for ATP and application in targeted photothermal therapy in the NIR-II window. ACS Macro Letters, 2020, 9(11): 1558–1562

[34] Wei P , Czaplewska J A , Wang L , Schubert S , Brendel J C , Schubert U S . Straightforward access to glycosylated, acid sensitive nanogels by host-guest interactions with sugar-modified pillar[5]arenes. ACS Macro Letters, 2020, 9(4): 540–545

[35] Peng H , Xie B , Yang X , Dai J , Wei G , He Y . Pillar[5]arene-based, dual pH and enzyme responsive supramolecular vesicles for targeted antibiotic delivery against intracellular MRSA. Chemical Communications (Cambridge), 2020, 56(58): 8115–8118

[36] Guo S , Huang Q , Wei J , Wang S , Wang Y , Wang L , Wang R . Efficient intracellular delivery of native proteins facilitated by preorganized guanidiniums on pillar[5]arene skeleton. Nano Today, 2022, 43: 101396

[37] Lu B , Huang Y , Quan H , Xia J , Wang J , Ding Y , Wang Y , Yao Y . Mitochondria-targeting multimodal phototheranostics based on triphenylphosphonium cation modified amphiphilic pillararenes and A–D–A fused-ring photosensitizers. ACS Macro Letters, 2023, 12(10): 1365–1371

[38] Chao S , Shen Z , Li B , Pei Y , Pei Z . An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer for synergistically enhanced cancer therapeutic effectiveness. Chemical Communications, 2023, 59(23): 3455–3458

[39] Chao S , Shen Z , Pei Y , Lv Y , Chen X , Ren J , Yang K , Pei Z . Pillar[5]arene-based supramolecular photosensitizer for enhanced hypoxic-tumor therapeutic effectiveness. Chemical Communications (Cambridge), 2021, 57(62): 7625–7628

[40] Yu G , Yu W , Shao L , Zhang Z , Chi X , Mao Z , Gao C , Huang F . Fabrication of a targeted drug delivery system from a pillar[5]arene-based supramolecular diblock copolymeric amphiphile for effective cancer therapy. Advanced Functional Materials, 2016, 26(48): 8999–9008

[41] Wu X , Zhang Y , Lu Y , Pang S , Yang K , Tian Z , Pei Y , Qu Y , Wang F , Pei Z . Synergistic and targeted drug delivery based on nano-CeO₂ capped with galactose functionalized pillar[5]arene via host-guest interactions. Journal of Materials Chemistry B: Materials for Biology and Medicine, 2017, 5(19): 3483–3487

[42] Peng H , Xie B , Cen X , Dai J , Dai Y , Yang X , He Y . Glutathione-responsive multifunctional nanoparticles based on mannose-modified pillar[5]arene for targeted antibiotic delivery against intracellular methicillin-resistant S. aureus. Materials Chemistry Frontiers, 2022, 6(3): 360–367

[43] Chao S , Huang P , Shen Z , Pei Y , Lv Y , Lu Y , Pei Z . A mannose-functionalized pillar[5]arene-based supramolecular fluorescent probe for real-time monitoring of gemcitabine delivery to cancer cells. Organic Chemistry Frontiers: An International Journal of Organic Chemistry, 2023, 10(14): 3491–3497

[44] Li J , Lv X , Li J , Jin W , Chen Z , Wen Y , Pei Z , Pei Y . A supramolecular near-infrared nanophotosensitizer from host-guest complex of lactose-capped pillar[5]arene with aza-bodipy derivative for tumor eradication. Organic Chemistry Frontiers: An International Journal of Organic Chemistry, 2023, 10(8): 1927–1935

[45] Yu M , Cao R , Ma Z , Zhu M . Development of “smart” drug delivery systems for Chemo/PDT synergistic treatment. Journal of Materials Chemistry B: Materials for Biology and Medicine, 2023, 11(7): 1416–1433

[46] Wang Q , Tian L , Xu J , Xia B , Li J , Lu F , Lu X , Wang W , Huang W , Fan Q . Multifunctional supramolecular vesicles for combined photothermal/photodynamic/hypoxia-activated chemotherapy. Chemical Communications, 2018, 54(73): 10328–10331

[47] Quan H , Huang Y , Xia J , Yang J , Lu B , Liu P , Yao Y . Integrating pillar[5]arene and bodipy for a supramolecular nanoplatform to achieve synergistic photodynamic therapy and chemotherapy. ChemBioChem, 2023, 24(19): 202300461

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