Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of α-MSH

Vagner, Josef; Handl, Heather L.; Gillies, Robert J.; Hruby, Victor J.

doi:10.1016/j.bmcl.2003.09.079

Cited by 62 publications

(89 citation statements)

References 9 publications

(7 reference statements)

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“…However, PEGylation also reduced the receptor binding affi nity of the RGD peptide sequence. We then applied a polyvalency effect to develop dimeric and multimeric RGD peptide sequences (22)(23)(24)(25)(26)(27)(28), with repeating cyclic pentapeptide units connected by glutamates.…”

Section: Methodsmentioning

confidence: 99%

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels

Mittra¹,

Goris²,

Iagaru³

et al. 2011

Radiology

127

122

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Purpose:To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fl uorine 18 ( 18 F) FPPRGD2 (2-fl uoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets a v b 3 integrin, in the fi rst volunteers imaged with this tracer. Materials and Methods:The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi 6 3. Results:The administration of With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% 6 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 6 0.096).

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Section: Methodsmentioning

confidence: 99%

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels

Mittra¹,

Goris²,

Iagaru³

et al. 2011

Radiology

127

122

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“…Previous work has demonstrated that two functionally unrelated GPCRs, i.e., MC4R and CCK2R, or MC4R and the δ-opioid receptor (δ-OR), can be noncovalently cross-linked by their corresponding heterobivalent ligands with high avidity (12,17,19). Multivalency can increase binding avidity, but not necessarily increase targeting specificity (32,33). By following the previous in vitro findings, the current work studied the parameters including linker length and flexibility, surface receptor expression level per cell, ratio of receptor expression level, receptor-ligand affinity, and ligand concentration on which this targeting specificity depends.…”

Section: Discussionmentioning

confidence: 99%

Heterobivalent ligands target cell-surface receptor combinations in vivo

Josan

Vagner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A challenge in tumor targeting is to deliver payloads to cancers while sparing normal tissues. A limited number of antibodies appear to meet this challenge as therapeutics themselves or as drug-antibody conjugates. However, antibodies suffer from their large size, which can lead to unfavorable pharmacokinetics for some therapeutic payloads, and that they are targeted against only a single epitope, which can reduce their selectivity and specificity. Here, we propose an alternative targeting approach based on patterns of cell surface proteins to rationally develop small, synthetic heteromultivalent ligands (htMVLs) that target multiple receptors simultaneously. To gain insight into the multivalent ligand strategy in vivo, we have generated synthetic htMVLs that contain melanocortin (MSH) and cholecystokinin (CCK) pharmacophores that are connected via a fluorescent labeled, rationally designed synthetic linker. These ligands were tested in an experimental animal model containing tumors that expressed only one (control) or both (target) MSH and CCK receptors. After systemic injection of the htMVL in tumor-bearing mice, label was highly retained in tumors that expressed both, compared with one, target receptors. Selectivity was quantified by using ex vivo measurement of Europium-labeled htMVL, which had up to 12-fold higher specificity for dual compared with single receptor expressing cells. This proof-of-principle study provides in vivo evidence that small, rationally designed bivalent htMVLs can be used to selectively target cells that express both, compared with single complimentary cell surface targets. These data open the possibility that specific combinations of targets on tumors can be identified and selectively targeted using htMVLs.receptor targeting | multivalency | cross-linking | gene expression profiling

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“…Multivalent interactions are frequently used in nature to increase the affinity of weak ligand-receptor interactions, 16,17) and multimerization has become a principal strategy for the development of cyclic RGD peptides (cRGD) for targeting integrin a V b 3 .…”

Section: )mentioning

confidence: 99%

“…[12][13][14] FN has been found to serve as a ligand for many integrins including a 3 b 1 , a 5 b 1 , a 8 b 1 , a V b 1 , a V b 3 , a V b 5 , a V b 6 and a IIb b 3 via its RGD motif. 15) Multivalent interactions are frequently used in nature to increase the affinity of weak ligand-receptor interactions, 16,17) and multimerization has become a principal strategy for the development of cyclic RGD peptides (cRGD) for targeting integrin a V b 3 . 18) This protein is highly expressed on activated endothelial cells during angiogenesis, 19,20) a requirement for tumor growth and metastasis, and also frequently overexpressed on many types of tumor cells.…”

mentioning

confidence: 99%

Effect of Multimerization of a Linear Arg-Gly-Asp Peptide on Integrin Binding Affinity and Specificity

Jin

Furukawa

Waki

et al. 2010

Biological & Pharmaceutical Bulletin

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Integrins are a family of transmembrane glycoproteins playing important roles in tumor invasion, metastasis, and neovascularization by mediating cell-extracellular matrix (ECM) interaction and initiating intracellular signaling. 1,2) Integrin consists of 2 noncovalently associated subunits (a and b), and currently 18 a and 8 b subunits have been identified in humans, which are able to form 24 distinct integrin heterodimers.3) Many integrins are known to recognize the tripeptide sequence Arg-Gly-Asp (RGD), which has been found in a wide variety of ECM proteins such as fibronectin (FN), vitronectin (VN), osteopontin, thrombospondin, fibrinogen, von Willebrand factor, collagens and laminin. 4,5) Recognition and binding between integrin receptor and RGD ligand may depend on intrinsic integrin affinity (via conformational changes) and spatial distribution of the ligands, which can be regulated by microenvironmental divalent cations and RGD-neighbouring sequence, respectively. 6,7)Various RGD-containing peptides have been increasingly developed for adapting to versatile applications including tumor imaging and therapy, drug delivery vector, targeted gene transfer, and biomaterial or tissue engineering. 3,[8][9][10][11] FN is a very important RGD-containing ECM protein, involved in malignant progression and metastasis, and used as a target for tumor therapy. [12][13][14] FN has been found to serve as a ligand for many integrins includingand a IIb b 3 via its RGD motif. 15)Multivalent interactions are frequently used in nature to increase the affinity of weak ligand-receptor interactions, 16,17) and multimerization has become a principal strategy for the development of cyclic RGD peptides (cRGD) for targeting integrin a V b 3 .18) This protein is highly expressed on activated endothelial cells during angiogenesis, 19,20) a requirement for tumor growth and metastasis, and also frequently overexpressed on many types of tumor cells.2,21) Its overexpression has been known to correlate well with tumor progression, invasion and metastasis. 2,22) In this study, we evaluated the effect of multimerization of a linear RGD peptide, Ala-ValThr-Gly-Arg-Gly-Asp-Ser-Tyr (AVTGRGDSY), on the binding affinity and specificity of integrin a V b 3 or b 1 , a subunit that forms complexes with various a integrin subunits, using a V b 3 -positive cells and a V b 3 -negative/b 1 -overexpressing cells. AVTGRGDSY was derived from the amino acid sequence AVTGRGDSP in FN, with "P" being replaced by the tyrosine residue "Y" for 125 I-labeling. Here we describe the synthesis of mono-, di-and trimeric AVTGRGDSY peptides, the radio-or fluorescence dye-labeling of these peptides, and evaluation of their biological characteristics both in vitro and in vivo. MATERIALS AND METHODS Synthesis of AVTGRGDSY PeptidesMonomeric AVT-GRGDSY peptide (RGD-monomer) was synthesized using peptide synthesizer by standard 9-fluorenylmethoxycarbonyl (Fmoc) method. The monomer was dissolved in dimethyl sulfoxide (DMSO) and pH was adjusted to 9 with triethylamine. Cross-link...

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Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of α-MSH

Cited by 62 publications

References 9 publications

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels

Heterobivalent ligands target cell-surface receptor combinations in vivo

Effect of Multimerization of a Linear Arg-Gly-Asp Peptide on Integrin Binding Affinity and Specificity

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Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of α-MSH

Cited by 62 publications

References 9 publications

Pilot Pharmacokinetic and Dosimetric Studies of18F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging αvβ3Integrin Levels

Pilot Pharmacokinetic and Dosimetric Studies of18F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging αvβ3Integrin Levels

Heterobivalent ligands target cell-surface receptor combinations in vivo

Effect of Multimerization of a Linear Arg-Gly-Asp Peptide on Integrin Binding Affinity and Specificity

Contact Info

Product

Resources

About

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels

Pilot Pharmacokinetic and Dosimetric Studies of¹⁸F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging α_vβ₃Integrin Levels