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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
In vitro and in vivo evaluation of Bombesin-MMAE conjugates for targeted tumour therapy
Jacopo Gomena1, Daniela Modena2, Paola Cordella2
1Hevesy György PhD School of Chemistry, Eötvös Loránd University, 1117, Budapest, Hungary; Eötvös Loránd University, Faculty of Science, Institute of Chemistry, 1117, Budapest, Hungary; HUN-REN-ELTE Research Group of Peptide Chemistry, 1117, Budapest, Hungary.
Abstract:
Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. The upregulation of the bombesin receptor 2 (BB2) in several malignancies and the advantages offered by peptide drug conjugates over antibody drug conjugates in terms of production and tumour targeting motivated us to synthesise and test bombesin conjugates armed with the tubulin binder monomethyl auristatin E. The widely used Val-Cit-PABC was initially included as cathepsin cleavable self-immolative linker for the release of the free drug. However, the poor stability of the Val-Cit-conjugates in mouse plasma encouraged us to consider the optimised alternatives Glu-Val-Cit-PABC and Glu-Gly-Cit-PABC. Conjugate BN-EVcM1, featuring Glu-Val-Cit-PABC, combined suitable stability (t(½) in mouse and human plasma: 8.4 h and 4.6 h, respectively), antiproliferative activity in vitro (IC50 = 29.6 nM on the human prostate cancer cell line PC-3) and the full release of the free payload within 24 h. Three conjugates, namely BN-EGcM1, BN-EVcM1 and BN-EVcM2, improved the accumulation of MMAE in PC-3 human prostate cancer xenograft mice models, compared to the administration of the free drug. Among them, BN-EVcM1 also stood out for the significantly extended survival of mice in in vivo acute efficacy studies and for the significant inhibition of the growth of a PC-3 tumour in mice in both acute and chronic efficacy studies.
Insights
New bombesin conjugates targeting the bombesin receptor 2 (BB2) show promise in prostate cancer therapy. BN-EVcM1 demonstrated stability, potent anti-cancer activity, and extended survival in mice, offering a potential advancement over traditional chemotherapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Targeted tumor therapy offers an alternative to conventional chemotherapy, with the bombesin receptor 2 (BB2) upregulated in several cancers.
- Peptide drug conjugates present advantages over antibody drug conjugates in production and tumor targeting.
Purpose of the Study:
- To synthesize and evaluate bombesin conjugates linked to the tubulin binder monomethyl auristatin E (MMAE) for targeted cancer therapy.
- To assess the stability, in vitro antiproliferative activity, and in vivo efficacy of novel conjugates.
Main Methods:
- Bombesin conjugates were synthesized using optimized linkers (Glu-Val-Cit-PABC and Glu-Gly-Cit-PABC) to improve stability compared to Val-Cit-PABC.
- In vitro antiproliferative activity was determined using the human prostate cancer cell line PC-3.
- In vivo studies involved evaluating MMAE accumulation in PC-3 xenograft mice and assessing acute and chronic efficacy, including survival studies.
Main Results:
- Conjugate BN-EVcM1 exhibited favorable plasma stability (t½ in mouse: 8.4 h; human: 4.6 h) and potent in vitro antiproliferative activity (IC50 = 29.6 nM on PC-3 cells).
- Three conjugates (BN-EGcM1, BN-EVcM1, BN-EVcM2) enhanced MMAE accumulation in PC-3 xenograft mice compared to the free drug.
- BN-EVcM1 significantly extended mouse survival and inhibited PC-3 tumor growth in both acute and chronic efficacy studies.
Conclusions:
- Optimized peptide drug conjugates, particularly BN-EVcM1, demonstrate significant potential for targeted prostate cancer therapy.
- BN-EVcM1 offers a promising therapeutic candidate due to its enhanced stability, potent efficacy, and improved in vivo performance.
- These findings support the development of bombesin-based peptide drug conjugates for treating BB2-expressing malignancies.
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