Targeting Using Integrins

The integrins represent another important cell surface molecule group for angiogenesis targeting because some integrins, such as avb3 and avb5, are upregulated on the endothelial cell surface of neovasculature.30,31 The avb3 integrin is expressed on numerous tumor cell types; it is highly expressed on neovascular endothelial cells. Hood and collaborators used 40-nm diameter cationic-lipid-based nanoparticles coupled to an organic avb3 ligand that was shown to be specific for avb3 in cell studies. These nanoparticles, which contained a luciferase reporter plasmid, were injected into mice with the avb3-negative cell line M21-L. The nanoparticles targeted to the neovasculature within the tumor (but not to the tumor cells themselves) with no expression elsewhere in the mice as detected by luciferase expression. In order to test therapeutic efficacy, NPs were conjugated to a mutant Raf gene that blocks angiogenesis. Systemic injection in the M21-L tumor-expressing mice rapidly induced apoptosis of endothelial cells within the tumor. Tumor regression was seen within 10 days.32

In the same study with VEGFR-2 targeting discussed above, Li and collaborators also demonstrated targeting of the radioisotope 90Y using nanoparticles targeted to the integrin avb3 with a small molecule integrin agonist.29 In mice with K1735-M2 tumors, avb3-targeted 90Y-nanoparticles significantly delayed tumor growth compared to untreated tumors. TUNEL staining of tumor sections showed widespread apoptosis in tumors treated with these targeted nanoparticles. The authors have postulated that this targeted nanoparticle radiotherapy has the potential to be used to treat a variety of solid tumors. They have also postulated that the use of nanoparticles increases efficacy due to the high payload delivered by the carriers.

Additionally, PEGylated polyethyleneimine (PEI) nanoplexes with a cyclic disulfide bond constrained Arg-Gly-Asp (RGD) peptide ligand at the distal end have been used to target integrin-expressing tumor neovasculature to deliver siRNA. Integrins are receptors for extracellular matrix components that contain a tripeptide RGD sequence. Therefore, RGD containing peptide sequences can target to cell surface integrins that are upregulated on neovasculature. The siRNA used inhibited angiogenesis by inhibiting VEGFR-2 expression. Intravenous injection of nanopar-ticles into nude mice with N2A tumors showed tumor uptake of the siRNA, inhibition of protein synthesis in the tumor, and inhibition of angiogenesis and tumor growth.33 This study demonstrates tumor selective delivery through both the targeting ligand and gene pathway by using siRNA.

In another avb3 targeting approach using an RGD peptide, Kopelman has created multifunctional nanoparticles of 30-60 nm for the treatment of gliomas.34 The nanoparticles are able to kill cancer cells by bombarding them with externally released reactive oxygen species created by photodynamic agents activated by laser light. The particles also contain superparamagnetic iron oxide and enhance imaging by magnetic resonance. The photodynamic sensitizer and MRI contrast agents are entrapped within a polyacrylamide core, the surface of which is coated with PEG chains and targeting RGD moieties. The particles containing photodynamic agents were shown to produce sufficient singlet oxygen to kill cells in vitro. Additionally, these nanoplatforms were injected into an in vivo rat intracerebral 9L tumor model, and diffusion MRI was performed at various times to evaluate the tumor diffusion, tumor growth, and tumor load. The gliomas treated with the nano-particles and irradiated with laser light caused regional necrosis and significant shrinkage of tumor mass, a shrinkage that lasted for 12 days. The authors postulate that the light activated release of reactive oxygen from photosensitizer-containing nanoparticles is a viable approach for brain tumor treatment. Also, the incorporation of MRI contrast agents allows for monitoring of treatment and tumor progression in vivo.

Carbohydrate based nanoparticles have also been used to target drugs to neovasculature via an avb3/cyclic RGD peptide interaction. Inulin multi-methacrylate formed the core of the nanoparti-cles and was attached to the RGD targeting moiety with a PEG linker. Doxorubicin was loaded in the nanoparticles via covalent and noncovalent linkages. The pharmacokinetics and biodistribution of the doxorubicin loaded nanoparticles were studied over five days in female Balb/cJ mice with metastatic mammary tumor clone-66. A bi-exponential fix with a terminal half-life of 5.99 h was observed; decreasing drug concentrations with time in the heart, lungs, kidney, and plasma was also observed. Conversely, increasing drug accumulation was observed in the liver, spleen, and in the tumor where there was also the presence of high levels of doxorubicin metabolite. The presence of the high metabolite levels in the tumorsuggests nothing more than tumor-specific nanoparticle degradation and release of drug.35

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