Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes - PubMed (original) (raw)
Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes
C Marty et al. Br J Cancer. 2002.
Abstract
We prepared small unilamellar liposomes derivatised with single chain antibody fragments specific for the ED-B domain of B-fibronectin. This extracellular matrix associated protein is expressed around newly forming blood vessels in the vicinity of many types of tumours. The single chain antibody fragments were functionalised by introduction of C-terminal cysteines and linked to liposomes via maleimide groups located at the terminal ends of poly(ethylene glycol) modified phospholipids. The properties of these anti-ED-B single chain antibody fragments-liposomes were analysed in vitro on ED-B fibronectin expressing Caco-2 cells and in vivo by studying their biodistribution and their therapeutic potential in mice bearing subcutanous F9 teratocarcinoma tumours. Radioactively labelled ((114m)Indium) single chain antibody fragments-liposomes accumulated in the tumours at 2-3-fold higher concentrations during the first 2 h after i.v. injection compared to unmodified liposomes. After 6-24 h both liposome types were found in similar amounts (8-10% injected dose g(-1)) in the tumours. Animals treated i.v. with single chain antibody fragments-liposomes containing the new cytotoxic agent 2'-deoxy-5-fluorouridylyl-N(4)-octadecyl-1-beta-D-arabinofuranosylcytosine (30 mg kg(-1) per dose, five times every 24 h) showed a reduction of tumour growth by 62-90% determined on days 5 and 8, respectively, compared to animals receiving control liposomes. Histological analysis revealed a marked reduction of F9 tumour cells and excessive deposition of fibronectin in the extracellular matrix after treatment with single chain antibody fragments-2-dioxy-5-fluorouridylyl-N(4)-octadecyl-1-beta-D-arabinofuranosylcytosine-liposomes. Single chain antibody fragments-liposomes targeted to ED-B fibronectin positive tumours therefore represent a promising and versatile novel drug delivery system for the treatment of tumours.
Copyright 2002 Cancer Research UK
Figures
Figure 3
Blood distribution curves (A) and tumour to blood ratios (B) of unmodified liposomes and scFv-liposomes. Mice (three per group) bearing s.c. F9 tumours were injected i.v. with 114mIn labelled liposomes. Results are expressed as % injected dose (%ID ml−1 ±s.e.m.) of radioactivity per millilitre blood or %ID g−1 ±s.e.m. tumour.
Figure 1
Binding of anti-ED-B scFv-liposomes to cells cultured for 48 h on collagen-I coated cover slips: (A, C, E) Phase contrast images of the sections shown in (B, D, F). ScFv-liposomes on ED-B positive Caco-2 cells (B) unmodified liposomes on ED-B positive Caco-2 cells (D) scFv-liposomes on ED-B negative Co-115 cells (F). Detection of specific binding was demonstrated by labelling the liposomes with the lipophilic fluorescent dye DiO. Magnification: ×400.
Figure 2
Tumour accumulation of unmodified liposomes and scFv-liposomes measured at different time points. Mice (three per group) bearing s.c. F9 tumours were injected with 114mIn labelled liposomes and killed after different time points. Results are expressed as % injected dose of radioactivity per gram tissue (%ID g−1). Open bars, control liposomes; closed bars, scFv-liposomes. At 1 and 2 h after injection the difference between the two preparations was statistically significant (*P<0.05; ±s.e.m.).
Figure 4
In vivo effects of liposome treatment on F9 tumour growth. Tumour bearing mice were treated five times every 24 h. Values represent the mean±s.e.m. of 5–10 treated mice. The tumour volumes were calculated by equation V=πab2/6 (a=largest tumour diameter, b=perpendicular diameter). Tumour volume values were converted in % change from baseline by equation Vt×100/V0 (Vt=volume at time t and V0=baseline volume). Statistical significant difference was found between empty liposomes and both 5-FdU-NOAC liposome preparations (* and # P<0.02; ±s.e.m.).
Figure 5
Histological analysis of F9 tumours treated with different liposome preparations. Tumours were excised 72 h after administration and sections stained with anti-ED-B scFv L19. Empty unmodified liposomes (A); empty scFv-liposomes (B); unmodified 5-FdU-NOAC-liposomes (C); scFv-5-FdU-NOAC-liposomes (D). Magnification: ×400.
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