Skip to main content

Advertisement

SpringerLink
Log in

Wheat germ agglutinin modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The combination of shikonin (SKN) and gefitinib (GFB) can reverse the drug resistance of lung cancer cells by affecting energy metabolism. However, the poor solubility of SKN and GFB limits their clinical application because of low bioavailability. Wheat germ agglutinin (WGA) can selectively bind to sialic acid and N-acetylglucosamine on the surfaces of microfold cells and enterocytes, and is a targeted biocompatible material. Therefore, we created a co-delivery micelle system called SKN/GFB@WGA-micelles with the intestinal targeting functions to enhance the oral absorption of SKN and GFB by promoting mucus penetration for nanoparticles via oral administration. In this study, Caco-2/HT29-MTX-E12 co-cultured cells were used to simulate a mucus/enterocyte dual-barrier environment, and HCC827/GR cells were used as a model of drug-resistant lung cancer. We aimed to evaluate the oral bioavailability and anti-tumor effect of SKN and GFB using the SKN/GFB@WGA-micelles system. In vitro and in vivo experimental results showed that WGA promoted the mucus penetration ability of micelles, significantly enhanced the uptake efficiency of enterocytes, improved the oral bioavailability of SKN and GFB, and exhibited good anti-tumor effects by reversing drug resistance. The SKN/GFB@WGA-micelles were stable in the gastrointestinal tract and provided a novel safe and effective drug delivery strategy.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Data will be available upon request.

References

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.

    Article  PubMed  Google Scholar 

  2. Tian X, Gu T, Lee MH, Dong Z. Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer. Biochim Biophys Acta Rev Cancer. 2022;1877:188645.

    Article  CAS  PubMed  Google Scholar 

  3. Wang C, Zhang Y, Chen W, Wang Y, Xing D. Epidermal growth factor receptor PROTACs as an effective strategy for cancer therapy: a review. Biochim Biophys Acta Rev Cancer. 2023;1878:188927.

    Article  CAS  PubMed  Google Scholar 

  4. Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, Ahn MJ, Vansteenkiste JF, Su WC, Felip E, Chia V, Glaser S, Pultar P, Zhao S, Peng B, Akimov M, Tan DSW. Phase Ib/II study of Capmatinib (INC280) plus Gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-Mutated, MET factor-dysregulated non-small-cell lung cancer. J Clin Oncol. 2018;36:3101–9.

    Article  CAS  PubMed  Google Scholar 

  5. Dong J, Qin Z, Zhang WD, Cheng G, Yehuda AG, Ashby CR Jr., Chen ZS, Cheng XD, Qin JJ. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: an update. Drug Resist Updat. 2020;49:100681.

    Article  PubMed  Google Scholar 

  6. Fan C, Zhang X, Upton Z. Anti-inflammatory effects of shikonin in human periodontal ligament cells. Pharm Biol. 2018;56:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhao X, Zhu Y, Hu J, Jiang L, Li L, Jia S, Zen K. Shikonin inhibits tumor growth in mice by suppressing pyruvate kinase M2-mediated aerobic glycolysis. Sci Rep. 2018;8:14517.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ai X, Hou X, Feng N. Combination of shikonin and gefitinib reverses drug resistance in human non-small cell lung cancer and its mechanism (in Chinese). China J Chin Materia Med. 2024;49:175–84. https://doi.org/10.19540/j.cnki.cjcmm.20230810.401

    Article  Google Scholar 

  9. Shirley M, Keam SJ. Aumolertinib: a review in Non-small Cell Lung Cancer. Drugs. 2022;82:577–84.

    Article  CAS  PubMed  Google Scholar 

  10. Biaoxue R, Shuanying Y, Wei L, Wei Z, Zongjuan M. Maintenance therapy of gefitinib for non-small-cell lung cancer after first-line chemotherapy regardless of epidermal growth factor receptor mutation: a review in Chinese patients. Curr Med Res Opin. 2012;28:1699–708.

    Article  PubMed  Google Scholar 

  11. Li H, Tong Y, Bai L, Ye L, Zhong L, Duan X, Zhu Y. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int J Biol Macromol. 2018;107:204–11.

    Article  CAS  PubMed  Google Scholar 

  12. Wang D, Jiang Q, Dong Z, Meng T, Hu F, Wang J, Yuan H. Nanocarriers transport across the gastrointestinal barriers: the contribution to oral bioavailability via blood circulation and lymphatic pathway. Adv Drug Deliv Rev. 2023;203:115130.

    Article  CAS  PubMed  Google Scholar 

  13. Ejazi SA, Louisthelmy R, Maisel K. Mechanisms of nanoparticle transport across intestinal tissue: an oral delivery perspective. ACS Nano. 2023;17:13044–61.

    Article  CAS  PubMed  Google Scholar 

  14. Alshammari MK, Almomen EY, Alshahrani KF, Altwalah SF, Kamal M, Al-Twallah MF, Alsanad SH, Al-Batti MH, Al-Rasheed FJ, Alsalamah AY, Alhazza MB, Alasmari FA, Abida M, Imran. Nano-enabled strategies for the treatment of lung cancer. Biomedicines: Potential Bottlenecks and Future Perspectives; 2023;11:473.

    Google Scholar 

  15. Delorme V, Lichon L, Mahindad H, Hunger S, Laroui N, Daurat M, Godefroy A, Coudane J, Gary-Bobo M, Van Den Berghe H. Reverse poly(epsilon-caprolactone)-g-dextran graft copolymers. Nano-carriers for intracellular uptake of anticancer drugs. Carbohydr Polym. 2020;232:115764.

    Article  CAS  PubMed  Google Scholar 

  16. Grimaudo MA, Pescina S, Padula C, Santi P, Concheiro A, Alvarez-Lorenzo C, Nicoli S. Poloxamer 407/TPGS mixed micelles as promising carriers for cyclosporine ocular delivery. Mol Pharm. 2018;15:571–84.

    Article  CAS  PubMed  Google Scholar 

  17. Liu Z, Wang H, Bu Y, Wu T, Chen X, Yan H, Lin Q. Fabrication of self-assembled micelles based on amphiphilic oxidized sodium alginate grafted oleoamine derivatives via Schiff base reduction amination reaction for delivery of hydrophobic food active ingredients. Int J Biol Macromol. 2023:128653.

  18. Joy R, Siddiqua H, Sharma S, Raveendran M, John F, Hassan PA, Gawali SL, Raghavan SC. George, block copolymer encapsulation of disarib, an inhibitor of bcl2 for improved chemotherapeutic potential. ACS Omega. 2023;8:40729–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gupta A, Costa AP, Xu X, Lee SL, Cruz CN, Bao Q, Burgess DJ. Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing. Int J Pharm. 2020;583:119340.

    Article  CAS  PubMed  Google Scholar 

  20. Stevens KC, Marras AE, Campagna TR, Ting JM, Tirrell MV. Effect of charged block length mismatch on double diblock polyelectrolyte complex micelle cores. Macromolecules. 2023;56:5557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fritz HF, Ortiz AC, Velaga SP, Morales JO. Preparation of a novel lipid-core micelle using a low-energy emulsification method. Drug Deliv Transl Res. 2018;8:1807–14.

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Y, Yang L, Yan Z, Deng X, Zhang J. Preparation and characterization of uricase in uricase-catalase liposomes prepared using borate buffer. Nan Fang Yi Ke Da Xue Bao. 2015;35:268–71.

    CAS  Google Scholar 

  23. Hou X, Cao B, He Y, Guo T, Li Z, Liu Y, Zhang Y, Feng N. Improved self-assembled micelles based on supercritical fluid technology as a novel oral delivery system for enhancing germacrone oral bioavailability. Int J Pharm. 2019;569:118586.

    Article  CAS  PubMed  Google Scholar 

  24. Kotta S, Aldawsari HM, Badr-Eldin SM, Nair AB, Yt K. Progress in polymeric micelles for drug delivery applications. Pharmaceutics. 2022;14.

  25. Kim TI, Kim TG, Lim DH, Kim SB, Park SM, Lim HJ, Kim HJ, Ki KS, Kwon EG, Kim YJ, Mayakrishnan V. The effect of nanoemulsified methionine and cysteine on the in vitro expression of casein in bovine mammary epithelial cells. Asian-Australas J Anim Sci. 2019;32:257–64.

    Article  CAS  PubMed  Google Scholar 

  26. Fan Z, Wu J, Fang X, Sha X. A new function of vitamin E-TPGS in the intestinal lymphatic transport of lipophilic drugs: enhancing the secretion of chylomicrons. Int J Pharm. 2013;445:141–7.

    Article  CAS  PubMed  Google Scholar 

  27. Chiu HI, Lim V. Wheat germ agglutinin-conjugated disulfide cross-linked alginate nanoparticles as a docetaxel carrier for colon cancer therapy. Int J Nanomed. 2021;16:2995–3020.

    Article  Google Scholar 

  28. Liu Y, Xie X, Hou X, Shen J, Shi J, Chen H, He Y, Wang Z, Feng N. Functional oral nanoparticles for delivering silibinin and cryptotanshinone against breast cancer lung metastasis. J Nanobiotechnol. 2020;18:83.

    Article  CAS  Google Scholar 

  29. Liu Y, Liu J, Liang J, Zhang M, Li Z, Wang Z, Dang B, Feng N. Mucosal transfer of wheat germ agglutinin modified lipid-polymer hybrid nanoparticles for oral delivery of oridonin. Nanomedicine. 2017;13:2219–29.

    Article  CAS  PubMed  Google Scholar 

  30. Akkus ZB, Nazir I, Jalil A, Tribus M, Bernkop-Schnurch A. Zeta potential changing polyphosphate nanoparticles: a promising approach to overcome the mucus and epithelial barrier. Mol Pharm. 2019;16:2817–25.

    Article  CAS  PubMed  Google Scholar 

  31. Raghu G, Berk M, Campochiaro PA, Jaeschke H, Marenzi G, Richeldi L, Wen FQ, Nicoletti F, Calverley PMA. The multifaceted therapeutic role of N-Acetylcysteine (NAC) in disorders characterized by oxidative stress. Curr Neuropharmacol. 2021;19:1202–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Trindade IC, Pound-Lana G, Pereira DGS, de Oliveira LAM, Andrade MS, Vilela JMC, Postacchini BB, Mosqueira VCF. Mechanisms of interaction of biodegradable polyester nanocapsules with non-phagocytic cells. Eur J Pharm Sci. 2018;124:89–104.

    Article  CAS  PubMed  Google Scholar 

  33. Wang CM, Fernez MT, Woolston BM, Carrier RL. Native gastrointestinal mucus: critical features and techniques for studying interactions with drugs, drug carriers, and bacteria. Adv Drug Deliv Rev. 2023;200:114966.

    Article  CAS  PubMed  Google Scholar 

  34. Guo S, Liang Y, Liu L, Yin M, Wang A, Sun K, Li Y, Shi Y. Research on the fate of polymeric nanoparticles in the process of the intestinal absorption based on model nanoparticles with various characteristics: size, surface charge and pro-hydrophobics. J Nanobiotechnol. 2021;19:32.

    Article  CAS  Google Scholar 

  35. des Rieux A, Ragnarsson EG, Gullberg E, Preat V, Schneider YJ, Artursson P. Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium. Eur J Pharm Sci. 2005;25:455–65.

    Article  CAS  PubMed  Google Scholar 

  36. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64:557–70.

    Article  CAS  PubMed  Google Scholar 

  37. Perumal S, Atchudan R, Lee W. A review of polymeric micelles and their applications. Polymers (Basel). 2022;14.

  38. Jin Y, Wu Z, Li C, Zhou W, Shaw JP, Baguley BC, Liu J, Zhang W. Optimization of weight ratio for DSPE-PEG/TPGS hybrid micelles to improve drug retention and tumor penetration. Pharm Res. 2018;35:13.

    Article  PubMed  Google Scholar 

  39. Alexander S, Cosgrove T, Prescott SW, Castle TC. Flurbiprofen encapsulation using pluronic triblock copolymers. Langmuir. 2011;27:8054–60.

    Article  CAS  PubMed  Google Scholar 

  40. Birch D, Diedrichsen RG, Christophersen PC, Mu H, Nielsen HM. Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium. Eur J Pharm Sci. 2018;118:144–53.

    Article  CAS  PubMed  Google Scholar 

  41. Liu J, Werner U, Funke M, Besenius M, Saaby L, Fano M, Mu H, Mullertz A. SEDDS for intestinal absorption of insulin: application of Caco-2 and Caco-2/HT29 co-culture monolayers and intra-jejunal instillation in rats. Int J Pharm. 2019;560:377–84.

    Article  CAS  PubMed  Google Scholar 

  42. Song Q, Yao L, Huang M, Hu Q, Lu Q, Wu B, Qi H, Rong Z, Jiang X, Gao X, Chen J, Chen H. Mechanisms of transcellular transport of wheat germ agglutinin-functionalized polymeric nanoparticles in Caco-2 cells. Biomaterials. 2012;33:6769–82.

    Article  CAS  PubMed  Google Scholar 

  43. Shen C, Chen R, Qian Z, Meng X, Hu T, Li Y, Chen Z, Huang C, Hu C, Li J. Intestinal absorption mechanisms of MTBH, a novel hesperetin derivative, in Caco-2 cells, and potential involvement of monocarboxylate transporter 1 and multidrug resistance protein 2. Eur J Pharm Sci. 2015;78:214–24.

    Article  CAS  PubMed  Google Scholar 

  44. Sato K, Nagai J, Mitsui N, Ryoko Y, Takano M. Effects of endocytosis inhibitors on internalization of human IgG by Caco-2 human intestinal epithelial cells. Life Sci. 2009;85:800–7.

    Article  CAS  PubMed  Google Scholar 

  45. Perfecto A, Rodriguez-Ramiro I, Rodriguez-Celma J, Sharp P, Balk J, Fairweather-Tait S. Pea ferritin stability under gastric pH conditions determines the mechanism of iron uptake in Caco-2 cells. J Nutr. 2018;148:1229–35.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mandeep S, Kaur SK, Samal S, Roy AT, Sangamwar. Successful oral delivery of fexofenadine hydrochloride by improving permeability via phospholipid complexation. Eur J Pharm Sci. 2020;149:105338.

    Article  CAS  PubMed  Google Scholar 

  47. Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev. 2001;46:27–43.

    Article  CAS  PubMed  Google Scholar 

  48. Yu H, Huang Q. Investigation of the absorption mechanism of solubilized curcumin using Caco-2 cell monolayers. J Agric Food Chem. 2011;59:9120–6.

    Article  CAS  PubMed  Google Scholar 

  49. Yan D. Hope and Challenges: Immunotherapy in EGFR-Mutant NSCLC patients. Biomedicines. 2023;11.

  50. Ni J, Zhou LL, Ding L, Zhang XQ, Zhao X, Li H, Cao H, Liu S, Wang Z, Ma R, Wu J, Feng J. Efatutazone and T0901317 exert synergistically therapeutic effects in acquired gefitinib-resistant lung adenocarcinoma cells. Cancer Med. 2018;7:1955–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li Q, Niu JQ, Jia JH, Xu W, Bai M, Yao GD, Song SJ. A highly oxidized germacranolide from elephantopus tomentosus inhibits the growth of hepatocellular carcinoma cells by targeting EGFR in vitro and in vivo. Bioorg Chem. 2023;143:107007.

    Article  PubMed  Google Scholar 

  52. Atal S, Asokan P, Jhaj R. Recent advances in targeted small-molecule inhibitor therapy for non-small-cell lung cancer-an update. J Clin Pharm Ther. 2020;45:580–4.

    Article  PubMed  Google Scholar 

  53. Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene. 2011;30:4297–306.

    Article  CAS  PubMed  Google Scholar 

  54. Kumar A, Gupta P, Rana M, Chandra T, Dikshit M, Barthwal MK. Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation. J Lipid Res. 2020;61:351–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Essogmo FE, Zhilenkova AV, Tchawe YSN, Owoicho AM, Rusanov AS, Boroda A, Pirogova YN, Sangadzhieva ZD, Sanikovich VD, Bagmet NN, Sekacheva MI. Cytokine profile in lung cancer patients: anti-tumor and oncogenic cytokines. Cancers (Basel). 2023;15.

  56. Zhao LY, Zhang WM. Recent progress in drug delivery of pluronic P123: pharmaceutical perspectives. J Drug Target. 2017;25:471–84.

    Article  CAS  PubMed  Google Scholar 

  57. Flood D, Lee ES, Taylor CT. Intracellular energy production and distribution in hypoxia. J Biol Chem. 2023;299:105103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Guo X, Tu P, Zhu L, Cheng C, Jiang W, Du C, Wang X, Qiu X, Luo Y, Wan L, Tang R, Ran H, Wang Z, Ren J. Nanoenabled tumor energy metabolism disorder via sonodynamic therapy for multidrug resistance reversal and metastasis inhibition. ACS Appl Mater Interfaces. 2023;15:309–26.

    Article  CAS  PubMed  Google Scholar 

  59. Peng L, Xu Q, Yin S, Zhang Y, Wu H, Liu Y, Chen L, Hu Y, Yuan J, Peng K, Lin Q. The emerging nanomedicine-based technology for non-small cell lung cancer immunotherapy: how far are we from an effective treatment. Front Oncol. 2023;13:1153319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shukla S, Chen ZS, Ambudkar SV. Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updat. 2012;15:70–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tang D, Subramanian J, Haley B, Baker J, Luo L, Hsu W, Liu P, Sandoval W, Laird MW, Snedecor B, Shiratori M, Misaghi S. Pyruvate kinase muscle-1 expression appears to drive lactogenic behavior in CHO cell lines, triggering lower viability and productivity: a case study. Biotechnol J. 2019;14:e1800332.

    Article  PubMed  Google Scholar 

  62. Icard P, Simula L, Fournel L, Leroy K, Lupo A, Damotte D, Charpentier MC, Durdux C, Loi M, Schussler O, Chassagnon G, Coquerel A, Lincet H, De Pauw V, Alifano M. The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: therapeutic implications. Drug Resist Updat. 2022;63:100852.

    Article  CAS  PubMed  Google Scholar 

  63. Zhou D, Duan Z, Li Z, Ge F, Wei R, Kong L. The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment. Front Pharmacol. 2022;13:1091779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (82074279), Natural Science Foundation of Shanghai (20ZR1458300), the Program for Shanghai High-Level Local University Innovation Team (SZY20220315) and the Anhui Provincial Natural Science Foundation (2208085QH270).

Author information

Author notes

  1. Xuefeng Hou and Xinyi Ai contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, NO. 1200 Cailun Road, Shanghai, 201203, China

    Xuefeng Hou, Xinyi Ai, Zhenda Liu, Jiayi Yang, Yihan Wu, Di Zhang & Nianping Feng

  2. School of Pharmacy, Wannan Medical College, Wuhu, 241002, China

    Xuefeng Hou

Authors
  1. Xuefeng Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyi Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenda Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiayi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yihan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Di Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nianping Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xuefeng Hou: Conceptualization, Methodology, Writing–review & editing. Xinyi Ai: Data curation, Writing– original draft. Zhenda Liu: Validation. Jiayi Yang: Visualization. Yihan Wu: Validation. Di Zhang: Visualization. Nianping Feng: Supervision, Project administration.

Corresponding author

Correspondence to Nianping Feng.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

Male Sprague–Dawley rats weighing 180–200 g were provided by Shanghai Slack Laboratory Animal Co., Ltd. (Shanghai, China) and raised at the Shanghai University of Traditional Chinese Medicine (permit SCXK [Hu] 2017-0005) under the ethics number PZSHUTCM211213013. Male BALB/c nude mice weighing 18–20 g were provided by Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and raised at Shanghai Southern Model Biotechnology Co., Ltd. (permit SCXK [Jing] 2016–0011) under the ethics number 2019-W9-5297. Before the experiments, all animals were raised in a controlled environment with a relative humidity of 55 ± 10% and a temperature of 23 ± 2 °C for at least one week, strictly adhering to the guidelines set forth by the Animal Ethical Committee.

Consent for publication

The authors declare that all authors have been actively involved in the work leading to this paper and all take responsibility for the published work.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, X., Ai, X., Liu, Z. et al. Wheat germ agglutinin modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01602-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01602-0

Keywords

Search

Navigation