Skip to main content

Advertisement

SpringerLink
Log in

Nanoliposomal Bcl-xL proteolysis-targeting chimera enhances anti-cancer effects on cervical and breast cancer without on-target toxicities

  • Research
  • Published:
Advanced Composites and Hybrid Materials Aims and scope Submit manuscript

Abstract

Bcl-xL is a well-characterized target gene of cancer. DT2216, a selective proteolysis-targeting chimera (PROTAC) has been developed for targeting Bcl-xL without causing pronounced thrombocytopenia. However, like most PROTACs, DT2216 has its intrinsic limitations such as low permeability, poor solubility, low bioavailability, and nonspecific biological distribution. In this study, a novel nanoliposome (NP)-encapsulated DT2216 (DT@NPs) was developed and the anti-cancer effects and safety of DT@NPs in vitro and in vivo were assessed. The DT@NPs had notable cytocompatibility in normal cells and good bioavailability in cancer cells. Compared with DT2216, DT@NPs exhibited an enhanced ability to degrade Bcl-xL in two cervical cancer cell lines (C33A and SiHa) and a triple-negative breast cancer cell line (MDA-MB-231), resulting in notably enhanced cytotoxicity for cancer cells, in particular, for MDA-MB-231. The apoptosis, colony formation, and wound healing assays showed that DT@NPs had a stronger effect on inducing apoptosis, suppressing colony formation, and inhibiting cellular migration than DT2216. Moreover, a notable inhibition of DT@NPs on tumor growth was observed in the tumor-bearing murine model. A high accumulation of Cy5-labeled DT@NPs in the tumor indicated that DT@NPs had a good biodistribution in vivo. DT@NPs showed stronger inhibition of tumor growth than DT2216 by enhancing the Bcl-xL degradation and apoptosis. The comprehensive safety assessments in histology, blood cell count, and the biochemical indicators of peripheral blood suggested that DT@NPs showed no appreciable on-target toxicities and side effects. In conclusion, nanoliposomal Bcl-xL targeted PROTAC enhanced anti-cancer effects on cervical and breast cancer without causing on-target toxicities.

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
Fig. 9

Similar content being viewed by others

Data availability

The data are available from the corresponding author upon reasonable request.

References

  1. Carneiro BA, El-Deiry WS (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 17(7):395–417

    Article  Google Scholar 

  2. Zhang P, Zhang X, Liu X, Khan S, Zhou D, Zheng G (2020) PROTACs are effective in addressing the platelet toxicity associated with BCL-X(L) inhibitors. Explor Target Antitumor Ther 1(4):259–272

    Article  Google Scholar 

  3. Shamas-Din A, Kale J, Leber B, Andrews DW (2013) Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol 5(4):a008714

    Article  Google Scholar 

  4. Keitel U, Scheel A, Thomale J, Halpape R, Kaulfuss S, Scheel C, Dobbelstein M (2014) Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation. Oncotarget 5(23):11778–11791

    Article  Google Scholar 

  5. Kawiak A, Kostecka A (2022) Regulation of Bcl-2 family proteins in estrogen receptor-positive breast cancer and their implications in endocrine therapy. Cancers (Basel) 14(2)

  6. Chung CW, Dai H, Fernandez E, Tinworth CP, Churcher I, Cryan J, Denyer J, Harling JD, Konopacka A, Queisser MA et al (2020) Structural insights into PROTAC-mediated degradation of Bcl-xL. ACS Chem Biol 15(9):2316–2323

    Article  CAS  Google Scholar 

  7. Abdul Rahman SF, Xiang Lian BS, Mohana-Kumaran N (2020) Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment. Future Oncol 16(28):2235–2249

    Article  CAS  Google Scholar 

  8. Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H (2014) Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother Pharmacol 74(3):593–602

    Article  CAS  Google Scholar 

  9. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW et al (2007) Programmed anuclear cell death delimits platelet life span. Cell 128(6):1173–1186

    Article  CAS  Google Scholar 

  10. Schoenwaelder SM, Jarman KE, Gardiner EE, Hua M, Qiao J, White MJ, Josefsson EC, Alwis I, Ono A, Willcox A et al (2011) Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 118(6):1663–1674

    Article  CAS  Google Scholar 

  11. Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS et al (2019) A selective BCL-X(L) PROTAC degrader achieves safe and potent antitumor activity. Nat Med 25(12):1938–1947

    Article  CAS  Google Scholar 

  12. Chen Y, Tandon I, Heelan W, Wang Y, Tang W, Hu Q (2022) Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation. Chem Soc Rev 51(13):5330–5350

    Article  CAS  Google Scholar 

  13. Huang HT, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, Buckley DL, Cho JH, Ko E, Jang J et al (2018) A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol 25(1):88–99 e86

  14. Zeng S, Huang W, Zheng X, Liyan C, Zhang Z, Wang J, Shen Z (2021) Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges. Eur J Med Chem 210:112981

    Article  CAS  Google Scholar 

  15. Edmondson SD, Yang B, Fallan C (2019) Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorg Med Chem Lett 29(13):1555–1564

    Article  CAS  Google Scholar 

  16. Churcher I (2018) Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J Med Chem 61(2):444–452

    Article  CAS  Google Scholar 

  17. Bakadia BM, Zhong A, Li X, Boni BOO, Ahmed AAQ, Souho T, Zheng R, Shi Z, Shi D, Lamboni L et al (2022) Biodegradable and injectable poly(vinyl alcohol) microspheres in silk sericin-based hydrogel for the controlled release of antimicrobials: application to deep full-thickness burn wound healing. Adv Compos Hybrid Mater 5(4):2847–2872

    Article  CAS  Google Scholar 

  18. Chen J, Zhang G, Zhao Y, Zhou M, Zhong A, Sun J (2022) Promotion of skin regeneration through co-axial electrospun fibers loaded with basic fibroblast growth factor. Adv Compos Hybrid Mater 5(2):1111–1125

    Article  CAS  Google Scholar 

  19. Boni BOO, Lamboni L, Mao L, Bakadia BM, Shi Z, Yang G (2022) In vivo performance of microstructured bacterial cellulose-silk sericin wound dressing: effects on fibrosis and scar formation. Eng Sci 19:175–185

    Google Scholar 

  20. Boni BOO, Lamboni L, Bakadia BM, Hussein SA, Yang G (2020) Combining silk sericin and surface micropatterns in bacterial cellulose dressings to control fibrosis and enhance wound healing. Eng Sci 10:68–77

    CAS  Google Scholar 

  21. Zhang C, He S, Zeng Z, Cheng P, Pu K (2022) Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy. Angew Chem Int Ed Engl 61(8):e202114957

    Article  CAS  Google Scholar 

  22. Jia W, Qi Y, Hu Z, Xiong Z, Luo Z, Xiang Z, Hu J, Lu W (2021) Facile fabrication of monodisperse CoFe2O4 nanocrystals@dopamine@DOX hybrids for magnetic-responsive on-demand cancer theranostic applications. Adv Compos Hybrid Mater 4(4):989–1001

    Article  CAS  Google Scholar 

  23. Wang X, Qi Y, Hu Z, Jiang L, Pan F, Xiang Z, Xiong Z, Jia W, Hu J, Lu W (2022) Fe3O4@PVP@DOX magnetic vortex hybrid nanostructures with magnetic-responsive heating and controlled drug delivery functions for precise medicine of cancers. Adv Compos Hybrid Mater 5(3):1786–1798

    Article  CAS  Google Scholar 

  24. Satpathy G, Ch GK (2022) ra r, Elayaraja K, Mahapatra DR, Subramania A, Guo Z, Umapathy S, Manik E, an a: Nanoparticles and bacterial interaction of host-pathogens and the detection enhancement of biomolecules by fluorescence Raman spectroscopic investigation. Eng Sci 20:341–351

    CAS  Google Scholar 

  25. Lian Y, Wang L, Cao J, Liu T, Xu Z, Yang B, Huang T, Jiang X, Wu N (2021) Recent advances on the magnetic nanoparticle–based nanocomposites for magnetic induction hyperthermia of tumor: a short review. Adv Compos Hybrid Mater 4(4):925–937

    Article  CAS  Google Scholar 

  26. Amjadi I, Rabiee M, Hosseini MS (2013) Anticancer activity of nanoparticles based on PLGA and its co-polymer: in-vitro evaluation. Iran J Pharm Res 12(4):623–634

    CAS  Google Scholar 

  27. Garcia-Pinel B, Porras-Alcala C, Ortega-Rodriguez A, Sarabia F, Prados J, Melguizo C, Lopez-Romero JM (2019) Lipid-based nanoparticles: application and recent advances in cancer treatment. Nanomaterials (Basel) 9(4)

  28. Khodaverdi H, Zeini MS, Moghaddam MM, Vazifedust S, Akbariqomi M, Tebyaniyan H (2022) Lipid-based nanoparticles for the targeted delivery of anticancer drugs: a review. Curr Drug Deliv 19(10):1012–1033

    Article  CAS  Google Scholar 

  29. Rajpoot K (2020) Lipid-based nanoplatforms in cancer therapy: recent advances and applications. Curr Cancer Drug Targets 20(4):271–287

    Article  CAS  Google Scholar 

  30. Fang J, Islam W, Maeda H (2020) 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 157:142–160

    Article  CAS  Google Scholar 

  31. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284

    Article  CAS  Google Scholar 

  32. Tenchov R, Bird R, Curtze AE, Zhou Q (2021) Lipid nanoparticles horizontal line from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano 15(11):16982–17015

    Article  CAS  Google Scholar 

  33. Bessou M, Lopez J, Gadet R, Deygas M, Popgeorgiev N, Poncet D, Nougarede A, Billard P, Mikaelian I, Gonzalo P et al (2020) The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production. Oncogene 39(15):3056–3074

    Article  CAS  Google Scholar 

  34. Skov N, Alves CL, Ehmsen S, Ditzel HJ (2022) Aurora Kinase A and Bcl-xL inhibition suppresses metastasis in triple-negative breast cancer. Int J Mol Sci 23(17)

  35. Alcon C, Gomez Tejeda Zanudo J, Albert R, Wagle N, Scaltriti M, Letai A, Samitier J, Montero J (2021) ER+ breast cancer strongly depends on MCL-1 and BCL-xL anti-apoptotic proteins. Cells 10(7)

  36. Abdul Rahman SF, Muniandy K, Soo YK, Tiew EYH, Tan KX, Bates TE, Mohana-Kumaran N (2020) Co-inhibition of BCL-XL and MCL-1 with selective BCL-2 family inhibitors enhances cytotoxicity of cervical cancer cell lines. Biochem Biophys Rep 22:100756

    Google Scholar 

  37. Fouque A, Lepvrier E, Debure L, Gouriou Y, Malleter M, Delcroix V, Ovize M, Ducret T, Li C, Hammadi M et al (2016) The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria. Cell Death Differ 23(10):1702–1716

    Article  CAS  Google Scholar 

  38. Zhang C, Zeng Z, Cui D, He S, Jiang Y, Li J, Huang J, Pu K (2021) Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy. Nat Commun 12(1):2934

    Article  CAS  Google Scholar 

  39. He Y, Zan X, Miao J, Wang B, Wu Y, Shen Y, Chen X, Gou H, Zheng S, Huang N et al (2022) Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles. Mater Today Bio 16:100423

    Article  CAS  Google Scholar 

  40. Ickenstein LM, Garidel P (2019) Lipid-based nanoparticle formulations for small molecules and RNA drugs. Expert Opin Drug Deliv 16(11):1205–1226

    Article  CAS  Google Scholar 

  41. Li Z, Tan S, Li S, Shen Q, Wang K (2017) Cancer drug delivery in the nano era: an overview and perspectives (Review). Oncol Rep 38(2):611–624

    Article  CAS  Google Scholar 

  42. Lian T, Ho RJ (2001) Trends and developments in liposome drug delivery systems. J Pharm Sci 90(6):667–680

    Article  CAS  Google Scholar 

  43. Khan S, Kellish P, Connis N, Thummuri D, Wiegand J, Zhang P, Zhang X, Budamagunta V, Hua N, Yang Y et al (2023) Co-targeting BCL-X(L) and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice. Cell Death Discov 9(1):1

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (No. 81974463 and No. 81974409).

Author information

Author notes

  1. Jiaming Zhang and Baofang Zhang contributed equally to this work.

Authors and Affiliations

  1. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jiaming Zhang, Baofang Zhang, Congli Pu, Kexin Huang & Yingchao Zhao

  2. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jiaming Zhang, Baofang Zhang, Congli Pu, Kexin Huang & Yingchao Zhao

  3. Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jiaming Zhang

  4. School of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China

    Jiarui Cui

  5. Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Hongbo Wang

Authors
  1. Jiaming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baofang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Congli Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiarui Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kexin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongbo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yingchao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jiaming Zhang: conceptualization, data curation, formal analysis, visualization, and writing– review & editing; Baofang Zhang: investigation, data curation, software, and writing – original draft; Congli Pu: resources and supervision; Jiarui Cui: visualization; Kexin Huang: resources and supervision; Hongbo Wang: supervision, data curation, and funding acquisition; Yingchao Zhao: conceptualization, project administration, supervision, resources, funding acquisition, data curation, and writing – review & editing. All authors approved the final manuscript.

Corresponding authors

Correspondence to Hongbo Wang or Yingchao Zhao.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

42114_2023_649_MOESM1_ESM.tif

Supplementary file1 FigureS1. DT2216 and DT@NPs induce Bcl-xL degradation in time- and dose-dependent manners. (A) Western analyses of the expression of Bcl-xL in C33A, SiHa, and MDA-MB-231 cells treated with various doses of DT2216 for 24, 48, and 72 h. (B)Western analyses of the expression of Bcl-xL in C33A, SiHa, and MDA-MB-231cells treated with DT2216 (3 μM) for 24, 48, and 72 h. (C) Western analyses ofthe expression of Bcl-xL in C33A, SiHa, and MDA-MB-231 cells treated withvarious doses of DT@NPs for 24, 48, and 72 h. NPs indicate the blanknanoliposomal particles. (D) Western analyses of the expression of Bcl-xL inC33A, SiHa, and MDA-MB-231 cells treated with DT@NPs (1 μM) for 24, 48, and 72h. (TIF 1942 KB)

42114_2023_649_MOESM2_ESM.tif

Supplementary file2 FigureS2. Histological analyses of the effects of DT2216 and DT@NPs on major organs. Hematoxylin–Eosin (HE) staining of the major organs of the SiHa or MDA-MB-231 tumor-bearing BALB/c nude mice treated with PBS, NPs, DT2216 (12.5 mg per kgbody weight, q4d, i.v.) or DT@NPs (12.5 mg per kg body weight, q4d, i.v.). (TIF 49839 KB)

42114_2023_649_MOESM3_ESM.tif

Supplementary file3 FigureS3. Whole blood cell counts and hemoglobin levels of peripheral blood in SiHa or MDA-MB-231 tumor-bearing BALB/c nude mice treated with PBS, NPs, DT2216, orDT@NPs. WBC, white blood cell; LYM, lymphocyte; HGB, hemoglobin; RBC, red bloodcell (TIF 476 KB)

42114_2023_649_MOESM4_ESM.tif

Supplementary file4 Figure S4. Biochemical indicators of peripheral blood in SiHa or MDA-MB-231 tumor-bearing BALB/c nude mice treated with PBS, NPs, DT2216, or DT@NPs. ALT, alanine aminotransferase; AST, aspartateaminotransferase; BUN, blood urea nitrogen; CR, serum creatinine (TIF 470 KB)

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

Zhang, J., Zhang, B., Pu, C. et al. Nanoliposomal Bcl-xL proteolysis-targeting chimera enhances anti-cancer effects on cervical and breast cancer without on-target toxicities. Adv Compos Hybrid Mater 6, 78 (2023). https://doi.org/10.1007/s42114-023-00649-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s42114-023-00649-w

Keywords

Search

Navigation