Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2020 Nov 14

PMID 33187322

Citations 13

Authors

Yingnan Si

JiaShiung Guan

Yuanxin Xu

Kai Chen

Seulhee Kim

Lufang Zhou

Renata Jaskula-Sztul

X Margaret Liu

Affiliations

Soon will be listed here.

Abstract

Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC of 2.2-2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC of 3.1-4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.

Citing Articles

The Interplay Between the Oncogene and Ribosomal Proteins in Osteosarcoma Onset and Progression: Potential Mechanisms and Indication of Candidate Therapeutic Targets.

Guerrieri A, Hattinger C, Marchesini F, Melloni M, Serra M, Ibrahim T Int J Mol Sci. 2024; 25(22).

PMID: 39596100 PMC: 11593864. DOI: 10.3390/ijms252212031.

A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer.

Zhou Z, Si Y, Zhang J, Chen K, George A, Kim S Cancer Res. 2024; 84(22):3848-3863.

PMID: 39186778 PMC: 11565169. DOI: 10.1158/0008-5472.CAN-23-4099.

CXCR4: From Signaling to Clinical Applications in Neuroendocrine Neoplasms.

Sanchis-Pascual D, Del Olmo-Garcia M, Prado-Wohlwend S, Zac-Romero C, Segura Huerta A, Hernandez-Gil J Cancers (Basel). 2024; 16(10).

PMID: 38791878 PMC: 11120359. DOI: 10.3390/cancers16101799.

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Chen K, Ernst P, Kim S, Si Y, Varadkar T, Ringel M bioRxiv. 2024; .

PMID: 38585739 PMC: 10996521. DOI: 10.1101/2024.03.24.584499.

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.

Xu X, Zhang J, Wang T, Li J, Rong Y, Wang Y Acta Pharm Sin B. 2024; 14(4):1542-1559.

PMID: 38572098 PMC: 10985036. DOI: 10.1016/j.apsb.2023.11.029.

References

Hennrich U, Kopka K . Lutathera: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. Pharmaceuticals (Basel). 2019; 12(3). PMC: 6789871. DOI: 10.3390/ph12030114. View

Werner R, Kircher S, Higuchi T, Kircher M, Schirbel A, Wester H . CXCR4-Directed Imaging in Solid Tumors. Front Oncol. 2019; 9:770. PMC: 6702266. DOI: 10.3389/fonc.2019.00770. View

Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood M . Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29(4):341-5. DOI: 10.1038/nbt.1807. View

Pinchot S, Holen K, Sippel R, Chen H . Carcinoid tumors. Oncologist. 2008; 13(12):1255-69. PMC: 2901509. DOI: 10.1634/theoncologist.2008-0207. View

Rizzo F, Vesely C, Childs A, Marafioti T, Khan M, Mandair D . Circulating tumour cells and their association with bone metastases in patients with neuroendocrine tumours. Br J Cancer. 2019; 120(3):294-300. PMC: 6353867. DOI: 10.1038/s41416-018-0367-4. View

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View

Jaskula-Sztul R, Xu W, Chen G, Harrison A, Dammalapati A, Nair R . Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy. Biomaterials. 2016; 91:1-10. PMC: 4865460. DOI: 10.1016/j.biomaterials.2016.03.010. View

Si Y, Kim S, Zhang E, Tang Y, Jaskula-Sztul R, Markert J . Targeted Exosomes for Drug Delivery: Biomanufacturing, Surface Tagging, and Validation. Biotechnol J. 2019; 15(1):e1900163. DOI: 10.1002/biot.201900163. View

Werner R, Weich A, Higuchi T, Schmid J, Schirbel A, Lassmann M . Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach. Theranostics. 2017; 7(6):1489-1498. PMC: 5436508. DOI: 10.7150/thno.18754. View

10.

Sriram K, Insel P . G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?. Mol Pharmacol. 2018; 93(4):251-258. PMC: 5820538. DOI: 10.1124/mol.117.111062. View

11.

Yang J, Kan Y, Ge B, Yuan L, Li C, Zhao W . Diagnostic role of Gallium-68 DOTATOC and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis. Acta Radiol. 2013; 55(4):389-98. DOI: 10.1177/0284185113496679. View

12.

Xu W, Burke J, Pilla S, Chen H, Jaskula-Sztul R, Gong S . Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy. Nanoscale. 2013; 5(20):9924-33. PMC: 3867929. DOI: 10.1039/c3nr03102k. View

13.

Sherman S, Carr J, Wang D, ODorisio M, ODorisio T, Howe J . Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors. Surgery. 2013; 154(6):1206-13. PMC: 3881364. DOI: 10.1016/j.surg.2013.04.052. View

14.

Mai R, Kaemmerer D, Trager T, Neubauer E, Sanger J, Baum R . Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin. Sci Rep. 2019; 9(1):4339. PMC: 6416272. DOI: 10.1038/s41598-019-39607-2. View

15.

Eriksson B, Kloppel G, Krenning E, Ahlman H, Plockinger U, Wiedenmann B . Consensus guidelines for the management of patients with digestive neuroendocrine tumors--well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology. 2007; 87(1):8-19. DOI: 10.1159/000111034. View

16.

Woldemichael G, Turbyville T, Vasselli J, Linehan W, McMahon J . Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A. Neoplasia. 2012; 14(8):771-7. PMC: 3431183. DOI: 10.1593/neo.12852. View

17.

Kashyap M, Amaya-Chanaga C, Kumar D, Simmons B, Huser N, Gu Y . Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia. J Hematol Oncol. 2017; 10(1):112. PMC: 5438492. DOI: 10.1186/s13045-017-0435-x. View

18.

Isozaki T, Kiba T, Numata K, Saito S, Shimamura T, Kitamura T . Medullary thyroid carcinoma with multiple hepatic metastases: treatment with transcatheter arterial embolization and percutaneous ethanol injection. Intern Med. 1999; 38(1):17-21. DOI: 10.2169/internalmedicine.38.17. View

19.

Palanivel K, Kanimozhi V, Kadalmani B . Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol. 2014; 35(10):10159-67. DOI: 10.1007/s13277-014-2286-1. View

20.

Deeb D, Gao X, Liu Y, Zhang Y, Shaw J, Valeriote F . The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. Int J Oncol. 2016; 49(3):1139-47. DOI: 10.3892/ijo.2016.3587. View