Targeting of immunoliposomes to endothelial cells expressing VCAM: a future strategy in cancer therapy

Gosk, Sara; Gottstein, Claudia; Bendas, Gerd

doi:10.5414/cpp43581

Cited by 6 publications

(4 citation statements)

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“…Importantly, VCAM-1 participates in other inflammatory conditions including atherogenesis14, 15, transplant rejection16 and cancer17, where therapeutic VCAM-1 targeting may also be effective18, 19. More broadly, by modifying the ligand, MPIO-constructs could readily be adapted to image other endovascular targets that are differentially expressed in a broad range of pathologies.…”

Section: Discussionmentioning

confidence: 99%

In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide

McAteer

Sibson²,

Mühlen

et al. 2007

Nat Med

262

242

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Multiple sclerosis (MS) is a disease of the central nervous system that is associated with leukocyte recruitment and subsequent inflammation, demyelination and axonal loss. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and its ligand, α 4 β 1 integrin, are key mediators of leukocyte recruitment and new selective inhibitors that bind to the α 4 subunit of α 4 β 1 substantially reduce clinical relapse in MS. Urgently needed is a molecular imaging technique to accelerate diagnosis, quantify disease activity and guide specific therapy.We report in vivo detection of VCAM-1 in acute brain inflammation, using MRI in a mouse model, at a time when pathology is otherwise undetectable. Antibody-conjugated microparticles carrying a high payload of iron oxide provided potent, quantifiable contrast effects that delineated the architecture of activated cerebral blood vessels. Rapid clearance from blood resulted in minimal background contrast. This technology is adaptable to monitor expression of endovascular molecules in vivo in a range of pathologies.Multiple sclerosis (MS) is a disease of the central nervous system characterized by multifocal white matter lesions 1 . Current diagnostic criteria for MS, incorporating both clinical and magnetic resonance imaging (MRI) characteristics, require the demonstration of lesion dissemination in both time and space 2 , 3 T2-weighted and gadolinium-enhanced T1-weighted MRI detect some, but not all, lesions while advanced MRI techniques such as diffusion imaging 4 , magnetization transfer 5 and MR spectroscopy 6 may provide additional insights. However, these approaches are limited in two key respects: (1) they image downstream injury, reflecting relatively advanced pathology and (2) while providing an indication of severity, current imaging techniques can not accurately assess disease activity 7 .

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Section: Discussionmentioning

confidence: 99%

In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide

McAteer

Sibson²,

Mühlen

et al. 2007

Nat Med

262

242

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“…All scFv immunoliposomes described in the literature so far have been prepared from scFv′ molecules with the additional cysteine(s) located at the C-terminus ,,,,,, or have been conjugated through amino-reactive coupling reagents , . The use of cysteine residues engineered into the recombinant antibody molecule allows for a site-directed and oriented coupling compared to coupling to amino groups, which is undirected and might thus influence antigen-binding activity.…”

Section: Discussionmentioning

confidence: 99%

Novel Single-Chain Fv′ Formats for the Generation of Immunoliposomes by Site-Directed Coupling

et al. 2007

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Immunoliposomes generated by coupling of antibodies to the liposomal surface allow for an active targeting of entrapped compounds to diseased areas. Single-chain Fv fragments (scFv) represent the smallest part of an antibody containing the entire antigen-binding site. They can be coupled in a defined and site-directed manner through genetically engineered cysteine residues, for example, those added at the C-terminus. Here, we have performed a comparative analysis of various scFv' variants with cysteine residues present at the end of a C-terminal extension of varying length and composition (HC variants) or introduced in the linker sequence connecting the variable heavy and light chain domain (LC variants). Using a scFv fragment directed against fibroblast activation protein (FAP) as a model antibody, we could show that all variants can be employed for the generation of active immunoliposomes, although the presence of three additional cysteine residues in one scFv' molecule resulted in decreased binding of immunoliposomes compared to that of immunoliposomes generated with scFv' molecules containing only one additional cysteine residue. In order to further improve the scFv' format by reducing the number of additional amino acid residues, we also generated molecules with the hexahistidyl-tag incorporated into the linker sequence together with a cysteine residue either at position 1 or 3 of the linker sequence (LCH variants). These newly designed scFv' molecules may be particularly suitable for the generation of immunoliposomes and other antibody conjugates, limiting the number of additional residues in these antibody molecules to a minimum.

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“…through other reactive coupling reagents, like amino groups (Hu et al, 2006;Gosk et al, 2005). The conjugation by amino-reactive groups bears the risk of an undirected and nonorientated coupling and might influence the antigen-binding activity.…”

Section: Hc and Lc Variantsmentioning

confidence: 99%

Targeted lipid-coated nanoparticles: Delivery of tumor necrosis factor-functionalized particles to tumor cells

Messerschmidt

Musyanovych

Altvater

et al. 2009

Journal of Controlled Release

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Polymeric nanoparticles displaying tumor necrosis factor on their surface (TNF nanocytes) are useful carrier systems capable of mimicking the bioactivity of membrane-bound TNF. Thus, TNF nanocytes are potent activators of TNF receptor 1 and 2 leading to a striking enhancement of apoptosis. However, in vivo applications are hampered by potential systemic toxicity. Here, using TNF nanocytes as a model system, we developed a procedure to generate targeted lipid-coated particles (TLP) in which TNF activity is shielded. The TLPs generated here are composed of an inner single-chain TNF (scTNF)-functionalized, polymeric nanoparticle core surrounded by a lipid coat endowed with polyethylene glycol (PEG) for sterical stabilization and a single-chain Fv (scFv) fragment for targeting. Using a scFv directed against the tumor stroma marker fibroblast activation protein (FAP) we show that TLP and scTNF-TLP specifically bind to FAP-expressing, but not to FAP-negative cells. Lipid coating strongly reduced nonspecific binding of particles and scTNF-mediated cytotoxicity towards FAP-negative cells. In contrast, an increased cytotoxicity of TLP was observed for FAP-positive cells. Thus, through liposome encapsulation, nanoparticles carrying bioactive molecules, which are subject to nonselective uptake and activity towards various cells and tissues, can be converted into target cell-specific composite particles exhibiting a selective activity towards antigen-positive target cells. Besides safe and targeted delivery of death ligands such as TNF, TLP should be suitable for various diagnostic and therapeutic applications, which benefit from a targeted delivery of reagents embedded into the particle core or displayed on the core particle surface.

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Targeting of immunoliposomes to endothelial cells expressing VCAM: a future strategy in cancer therapy

Cited by 6 publications

References 0 publications

In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide

In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide

Novel Single-Chain Fv′ Formats for the Generation of Immunoliposomes by Site-Directed Coupling

Targeted lipid-coated nanoparticles: Delivery of tumor necrosis factor-functionalized particles to tumor cells

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