DOTA-tris(acid)-amido-dPEG®₂₄-amido-dPEG®₂₄-DSPE

DOTA-tris(acid)-amido-dPEG®24-amido-dPEG®24-DSPE, product number 11384, is designed incorporation of lanthanoid radionuclides into liposomes or micelles for transport and delivery. The molecule consists of the macrocycle 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) that is coupled to a single molecular weight, discrete polyethylene glycol (dPEG®) linker and terminated with 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).

DOTA
The use of radionuclides in diagnostic and therapeutic applications is becoming increasingly popular. DOTA, a highly popular bifunctional chelator, forms thermodynamically stable, kinetically inert complexes with Ln(III) ions. Thus, DOTA has become the preferred ligand for targeted radiopharmaceutical applications that use lanthanide or yttrium isotopes.
DSPE
Liposomes and micelles have transformed medical therapeutics and diagnostics. Liposomal and micellar nanoparticles with diameters of 30 – 200 nm possess numerous useful qualities for delivery of cytotoxic agents. These features include good in vivo stability; extended circulation time in blood; reduced systemic toxicity; and preferential accumulation in vascularized tumors through the enhanced permeation and retention (EPR) effect. Several liposomal and micellar formulations have been approved for clinical use.

DSPE is a highly popular lipid that is used in many different formulations of liposomes and micelles. It incorporates stably into the lipophilic layer of liposomes and micelles. Because of its stability in lipophilic layers and ease of modification of the hydrophilic head group, DSPE has become the preferred lipid for use in many different formulations of liposomes and micelles.

PEGylation
Despite their many useful, transformative properties, liposomes and micelles are vulnerable in vivo to opsonization and removal from the bloodstream through the mononuclear phagocytic system (MPS), more commonly known as the reticuloendothelial system (RES). Covalent attachment of polyethylene glycol (PEG; the process of attaching PEG to a molecule is known as PEGylation) to liposomal and micellar surfaces shields the coated surfaces by a steric barrier consisting of water and PEG. This steric barrier decreases or abolishes opsonization. Thus, PEGylation protects the liposomes and micelles from removal by the RES.

Disperse versus Discrete PEG
Traditional PEG is a polymer. Accordingly, polymeric PEG is disperse (Đ > 1), consisting of a complex mixture of different chain lengths and molecular weights. By contrast, our dPEG® products are single molecular weight compounds. Each dPEG® product contains a single, discrete PEG chain (Đ = 1), resulting in a uniform product. Our customers report anecdotally that dPEG® products are easier to analyze and use.

Polymeric PEG2000 (a polymer PEG having an average molecular weight of 2,000 Daltons) is normally used to coat liposomes and micelles. Typically, a density of 5 – 8 mole% is used for coating. Research at the University Of Notre Dame in the lab of Başar Bilgiçer demonstrates that this traditional PEG coating is not scientifically well reasoned. Two papers by Stefanik, et al., and one paper by Noble, et al., both in the Bilgiçer lab, systematically analyzed the effect of different PEG chain lengths and different degrees of PEGylation of liposomes. Our dPEG® products were used for this research. The research results established that smaller, dPEG® coatings provide PEGylated liposomes with levels of protection similar to polymeric PEG2000. Moreover, dPEG®-modified liposomes showed superior uptake of PEGylated liposomes compared to disperse PEG2000-modified liposomes.

DOTA-tris(acid)-amido-dPEG®24-amido-dPEG®24-DSPE
DOTA-tris(acid)-amido-dPEG®24-amido-dPEG®24-DSPE, PN11384, is designed for use in radionuclide-focused therapeutic or diagnostic applications. Paired with some of our other dPEG®-DSPE products, PN11384, can be formed into liposomes or micelles that deliver metal radioisotopes to targets of interest in vitro or in vivo. The dPEG® surface coating will reduce or eliminate opsonization. Consequently, more liposomes or micelles will reach the target, leading to higher effectiveness and lower dosing requirements.

If you need bulk product in a larger package size than our standard sizes, please contact us for a quote. Our commercial capabilities permit us to manufacture this product at any scale that you need.

Application References:

Hermanson, G. T. Chapter 18, PEGylation and Synthetic Polymer Modification. Bioconjugate Techniques, 3rd edition. Academic Press: New York, 2013, 787-838.
Hermanson, G. T. Chapter 21, Liposome Conjugates and Derivatives. Bioconjugate Techniques, 3rd edition. Academic Press: New York, 2013, 921-949.
De León-Rodríguez, L. M.; Kovacs, Z. The Synthesis and Chelation Chemistry of DOTA−Peptide Conjugates. Bioconjugate Chem. 2008, 19(2), 391–402. https://doi.org/10.1021/bc700328s.
Brechbiel, M. W. Bifunctional chelates for metal nuclides. The Quarterly Journal of Nuclear Medicine and Molecular Imaging 2008, 52(2), 166-173. https://www.minervamedica.it/en/journals/nuclear-med-molecular-imaging/article.php?cod=R39Y2008N02A0166 (accessed Feb 7, 2019).
Li, L.; Crow, D.; Turatti, F.; Bading, J. R.; Anderson, A.-L.; Poku, E.; Yazaki, P. J.; Carmichael, J.; Leong, D.; Wheatcroft, M. P.; et al. Site-Specific Conjugation of Monodispersed DOTA-PEGn to a Thiolated Diabody Reveals the Effect of Increasing PEG Size on Kidney Clearance and Tumor Uptake with Improved 64-Copper PET Imaging. Bioconjugate Chem. 2011, 22(4), 709–716. https://doi.org/10.1021/bc100464e.
Stefanick, J. F.; Ashley, J. D.; Kiziltepe, T.; Bilgicer, B. A Systematic Analysis of Peptide Linker Length and Liposomal Polyethylene Glycol Coating on Cellular Uptake of Peptide-Targeted Liposomes. ACS Nano 2013, 7(4), 2935–2947. https://doi.org/10.1021/nn305663e.
Stefanick, J. F.; Ashley, J. D.; Bilgicer, B. Enhanced Cellular Uptake of Peptide-Targeted Nanoparticles through Increased Peptide Hydrophilicity and Optimized Ethylene Glycol Peptide-Linker Length. ACS Nano 2013, 7(9), 8115–8127. https://doi.org/10.1021/nn4033954.
Noble, G. T.; Stefanick, J. F.; Ashley, J. D.; Kiziltepe, T.; Bilgicer, B. Ligand-Targeted Liposome Design: Challenges and Fundamental Considerations. Trends in Biotechnology 2014, 32(1), 32–45. https://doi.org/10.1016/j.tibtech.2013.09.007.
Saw, P. E.; Park, J.; Lee, E.; Ahn, S.; Lee, J.; Kim, H.; Kim, J.; Choi, M.; Farokhzad, O. C.; Jon, S. Effect of PEG Pairing on the Efficiency of Cancer-Targeting Liposomes. Theranostics 2015, 5(7), 746–754. https://doi.org/10.7150/thno.10732.
Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal Formulations in Clinical Use: An Updated Review. Pharmaceutics 2017, 9(2), 12. https://doi.org/10.3390/pharmaceutics9020012.

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