Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende Patientenratgeber
Erweiterte Suche
Anmelden
nach oben
Investigational New Drugs
Erschienen in:

05.08.2023 | Research

Enhanced antitumor and anti-metastasis by VEGFR2-targeted doxorubicin immunoliposome synergy with NK cell activation

verfasst von: Mingzhu Pan, Yali Liu, Tian Sang, Jiajun Xie, Huishu Lin, Jianpeng Wei, Shuai Shao, Yanying Zheng, Juan Zhang

Erschienen in: Investigational New Drugs | Ausgabe 5/2023

Einloggen, um Zugang zu erhalten

Summary

Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug’s lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2–MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.
Literatur
1.
Barenholz Y (2012) Doxil®–the first FDA-approved nano-drug: lessons learned. J Control Release 160(2):117–134PubMedCrossRef
2.
He H, Liu L, Morin E, Liu M (2019) Schwendeman AJAocr. Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures 52(9):2445–2461
3.
Gabizon AA, Patil Y, La-Beck NM (2016) New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updates 29:90–106CrossRef
4.
Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12(8):895–904PubMedCrossRef
5.
Füredi A, Szebényi K, Tóth S, Cserepes M, Hámori L, Nagy V et al (2017) Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. J Control Release 261:287–296PubMedCrossRef
6.
O’Brien MER, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A et al (2004) Reduced cardiotoxicity and comparable efficacy in a phase IIItrial of pegylated liposomal doxorubicin HCl(CAELYX™/Doxil®) versus conventional doxorubicin forfirst-line treatment of metastatic breast cancer. Ann Oncol 15(3):440–449PubMedCrossRef
7.
Sapra P, Allen TM (2002) Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. Can Res 62(24):7190–7194
8.
Park JW, Hong KL, Kirpotin DB, Colbern G, Shalaby R, Baselga J et al (2002) Anti-HER2 immunoliposomes: Enhanced efficacy attributable to targeted delivery. Clin Cancer Res 8(4):1172–1181PubMed
9.
Mamot C, Drummond DC, Greiser U, Hong K, Kirpotin DB, Marks JD et al (2003) Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. Can Res 63(12):3154–3161
10.
Heath T, Fraley R, Papahdjopoulos D (1980) Antibody targeting of liposomes: cell specificity obtained by conjugation of F(ab')2 to vesicle surface. Science 210(4469):539–541
11.
Xu C, Yang S, Jiang ZJ, Zhou JP, Yao J (2020) Self-propelled gemini-like LMWH-scaffold nanodrugs for overall tumor microenvironment manipulation via macrophage reprogramming and vessel normalization. Nano Lett 20(1):372–383PubMedCrossRef
12.
Yang DZ, Feng LZ, Dougherty CA, Luker KE, Chen DQ, Cauble MA et al (2016) In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide. Biomaterials 104:361–371PubMedPubMedCentralCrossRef
13.
Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F et al (2017) Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer. JAMA Oncol 3(4):509PubMedCrossRef
14.
Verschraegen CF, Czok S, Muller CY, Boyd L, Lee SJ, Rutledge T et al (2012) Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxane-resistant ovarian cancer. Ann Oncol 23(12):3104–3110PubMedCrossRef
15.
Moulder S, Moroney J, Helgason T, Wheler J, Booser D, Albarracin C et al (2011) Responses to Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Metaplastic Carcinoma of the Breast: Biologic Rationale and Implications for Stem-Cell Research in Breast Cancer. J Clin Oncol 29(19):e572–e575PubMedCrossRef
16.
Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I et al (2015) Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial. J Clin Oncol 33(32):3836–3838PubMedCrossRef
17.
Kudoh K, Takano M, Kouta H, Kikuchi R, Kita T, Miyamoto M et al (2011) Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers. Gynecol Oncol 122(2):233–237PubMedCrossRef
18.
Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligands and receptors: Review. Blood Cell Mol Dis 38(3):258–268CrossRef
19.
Hamerlik P, Lathia JD, Rasmussen R, Wu QL, Bartkova J, Lee M et al (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209(3):507–520PubMedPubMedCentralCrossRef
20.
21.
Zhang J, Li H, Wang X, Qi H, Miao X, Zhang T et al (2012) Phage-derived fully human antibody scFv fragment directed against human vascular endothelial growth factor receptor 2 blocked its interaction with VEGF. Biotechnol Prog 28(4):981–989PubMedCrossRef
22.
Xu Y, Zhang XR, Wang Y, Pan MZ, Wang M, Zhang J (2019) A VEGFR2-MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice. Cancer Immunol Immun 68(9):1429–1441CrossRef
23.
Pasquetto MV, Vecchia L, Covini D, Digilio R, Scotti C (2011) Targeted Drug Delivery Using Immunoconjugates: Principles and Applications. J Immunother 34(9):611–628PubMedCrossRef
24.
25.
Kirpotin D, Park JW, Hong K, Zalipsky S, Li WL, Carter P et al (1997) Sterically stabilized Anti-HER2 immunoliposomes: Design and targeting to human breast cancer cells in vitro. Biochemistry 36(1):66–75PubMedCrossRef
26.
Song X, Wan Z, Chen T, Fu Y, Jiang K, Yi X et al (2016) Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment. Biomaterials 108:44–56PubMedCrossRef
27.
Xu P, Yin Q, Shen J, Chen L, Yu H, Zhang Z et al (2013) Synergistic inhibition of breast cancer metastasis by silibinin-loaded lipid nanoparticles containing TPGS. Int J Pharm 454(1):21–30PubMedCrossRef
28.
Jiang K, Song X, Yang L, Li L, Wan Z, Sun X et al (2018) Enhanced antitumor and anti-metastasis efficacy against aggressive breast cancer with a fibronectin-targeting liposomal doxorubicin. J Control Release 271:21–30PubMedCrossRef
29.
Kocatürk B, Versteeg HH (2015) Orthotopic injection of breast cancer cells into the mammary fat pad of mice to study tumor growth. J Vis Exp (96):51967
30.
Cao X, Luo J, Gong T, Zhang ZR, Sun X, Fu Y (2015) Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo. Mol Pharm 12(1):274–286PubMedCrossRef
31.
Zhou A, Du J, Jiao M, Xie D, Wang Q, Xue L et al (2019) Co-delivery of TRAIL and siHSP70 using hierarchically modular assembly formulations achieves enhanced TRAIL-resistant cancer therapy. J Control Release 304:111–124PubMedCrossRef
32.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE et al (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 21(7):440–446PubMedPubMedCentralCrossRef
33.
Ramachandran C, Samy TS, Huang XL, Yuan ZK, Krishan A (1993) Doxorubicin-induced DNA breaks, topoisomerase II activity and gene expression in human melanoma cells. Biochem Pharmacol 45(6):1367–1371PubMedCrossRef
34.
Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S et al (2018) Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359(6383):1537–42
35.
Wang T, Sun F, Xie W, Tang M, He H, Jia X et al (2016) A bispecific protein rG7S-MICA recruits natural killer cells and enhances NKG2D-mediated immunosurveillance against hepatocellular carcinoma. Cancer Lett 372(2):166–178PubMedCrossRef
36.
Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 33(9):941–951PubMedPubMedCentralCrossRef
37.
Amreddy N, Babu A, Muralidharan R, Panneerselvam J, Srivastava A, Ahmed R et al (2018) Recent Advances in Nanoparticle-Based Cancer Drug and Gene Delivery. Adv Cancer Res 137:115–170PubMedCrossRef
38.
39.
Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discovery 4(2):145–160PubMedCrossRef
40.
Allen TM, Cullis PR (2013) Liposomal drug delivery systems: From concept to clinical applications. Adv Drug Deliv Rev 65(1):36–48PubMedCrossRef
41.
Park JW, Hong K, Kirpotin DB, Colbern G, Shalaby R, Baselga J et al (2002) Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. Clin Cancer Res 8(4):1172–1181PubMed
42.
Lu R-M, Hwang Y-C, Liu IJ, Lee C-C, Tsai H-Z, Li H-J et al (2020) Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27(1):1PubMedPubMedCentralCrossRef
43.
El Sharouni SY, Kal HB, Battermann JJ (2003) Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer 89(12):2184–9
44.
Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D et al (2014) Paclitaxel Therapy Promotes Breast Cancer Metastasis in a TLR4-Dependent Manner. Can Res 74(19):5421–5434CrossRef
45.
Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J et al (2017) Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene 36(5):639–651PubMedCrossRef
46.
Genet G, Boye K, Mathivet T, Ola R, Zhang F, Dubrac A et al (2019) Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis. Nat Commun 10(1):2350PubMedPubMedCentralCrossRef
47.
De Palma M, Biziato D, Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17(8):457–474PubMedCrossRef
48.
Gampel A, Moss L, Jones MC, Brunton V, Norman JC, Mellor H (2006) VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. Blood 108(8):2624–2631PubMedCrossRef
49.
Ma S, Pradeep S, Hu W, Zhang D, Coleman R, Sood A (2018) The role of tumor microenvironment in resistance to anti-angiogenic therapy. F1000Res 7:326
50.
Shimasaki N, Jain A, Campana D (2020) NK cells for cancer immunotherapy. Nat Rev Drug Discov 19(3):200–218PubMedCrossRef
Metadaten
Titel
Enhanced antitumor and anti-metastasis by VEGFR2-targeted doxorubicin immunoliposome synergy with NK cell activation
verfasst von
Mingzhu Pan
Yali Liu
Tian Sang
Jiajun Xie
Huishu Lin
Jianpeng Wei
Shuai Shao
Yanying Zheng
Juan Zhang
Publikationsdatum
05.08.2023
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 5/2023
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-023-01372-5

Weitere Artikel der Ausgabe 5/2023

Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper

  • Research

Cytotoxicity of poly-guanidine in medulloblastoma cell lines

  • Open Access
  • Research

A novel bivalent anti-c-MET/PD-1 bispecific antibody exhibits potent cytotoxicity against c-MET/PD-L1-positive colorectal cancer

  • Research

Clinical characteristics of liver injury induced by immune checkpoint inhibitors in patients with advanced biliary tract carcinoma

  • Research

Pharmacological assessment of the antineoplastic and immunomodulatory properties of a new spiroindolone derivative (7’,8’-Dimethoxy-1’,3’-dimethyl-1,2,3’,4’-tetrahydrospiro[indole-3,5’-pyrazolo[3,4-c]isoquinolin]-2-one) in chronic myeloid leukemia

  • Research

Lurbinectedin in patients with pretreated endometrial cancer: results from a phase 2 basket clinical trial and exploratory translational study

  • Open Access
  • Research

Neu im Fachgebiet Onkologie

KI-gestütztes Mammografiescreening überzeugt im Praxistest

Mit dem Einsatz künstlicher Intelligenz lässt sich die Detektionsrate im Mammografiescreening offenbar deutlich steigern. Mehr unnötige Zusatzuntersuchungen sind laut der Studie aus Deutschland nicht zu befürchten.

Welche Krebserkrankungen bei Zöliakie häufiger auftreten

Eine große Kohortenstudie hat den Zusammenhang zwischen Zöliakie und gastrointestinalen Krebserkrankungen und inflammatorischen Krankheiten untersucht. Neben gastrointestinalen Tumoren ist auch ein nicht solider Krebs häufiger.

Adjuvanter PD-L1-Hemmer verhindert Rezidive bei Hochrisiko-Urothelkarzinom

Sind Menschen mit muskelinvasivem Urothelkarzinom für die neoadjuvante platinbasierte Therapie nicht geeignet oder sprechen sie darauf nicht gut an, ist Pembrolizumab eine adjuvante Alternative: Die krankheitsfreie Lebenszeit wird dadurch mehr als verdoppelt.

Duale Checkpointhemmung gegen Melanome verlängert langfristig das Leben

Im Vergleich zu den Überlebenschancen vor der Einführung von Immuncheckpointhemmern (ICI) ist der Fortschritt durch eine ICI-Kombination mit unterschiedlichen Tagets bei fortgeschrittenem Melanom erstaunlich. Das belegen die finalen Ergebnisse der CheckMate-067-Studie und geben Betroffenen "Hoffnung auf Heilung".

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise