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Published on: January 7, 2019
A novel solid lipid nanoparticle formulation for active targeting to tumor α(v) β(3) integrin receptors reveals
Adam J Shuhendler1, Preethy Prasad, Michael Leung
1Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2.
Abstract:
The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications.
Insights
Targeting tumors with cyclic Arg-Gly-Asp (cRGD)-conjugated nanoparticles enhanced specificity but also increased off-target organ accumulation. This suggests potential for tumor neovascular therapies and imaging, despite a trade-off in overall tumor tissue distribution.
Area of Science:
- Nanomedicine
- Biotechnology
- Oncology
Background:
- Alpha-v beta-3 (α(v)β(3)) integrin receptors are overexpressed on tumor cells and vasculature, making them a target for cancer therapies.
- Nanoparticle-based drug delivery targeting integrins has shown limited therapeutic benefits.
- Solid lipid nanoparticles (SLN) offer a promising platform for targeted drug delivery.
Purpose of the Study:
- To develop novel α(v)β(3)-targeted near-infrared emitting SLN conjugated with cyclic Arg-Gly-Asp (cRGD).
- To assess the impact of cRGD conjugation on nanoparticle biodistribution and tumor uptake.
- To evaluate the potential of these targeted SLN for cancer imaging and therapy.
Main Methods:
- Conjugation of cRGD ligand to near-infrared emitting SLN.
- Preparation of non-targeted, actively targeted (RGD-SLN), and blocked RGD-SLN formulations.
- Intravenous injection into mice bearing human breast tumors.
- Assessment of tumor micropharmacokinetics using intravital microscopy.
- Whole-animal biodistribution analysis via optical imaging.
Main Results:
- RGD-SLN demonstrated increased specificity for tumor neovasculature and prolonged retention within tumors compared to non-targeted SLN.
- Significant accumulation of RGD-SLN was observed in the liver, spleen, and kidneys, exceeding that of non-targeted SLN.
- Despite increased off-target organ distribution, the enhanced tumor neovascular targeting and retention hold promise.
Conclusions:
- Active targeting of α(v)β(3) integrins with cRGD-SLN is a double-edged sword, improving tumor neovascular specificity but increasing off-target organ accumulation.
- The enhanced specificity and retention in tumor neovasculature suggest potential utility for neovascular-specific therapies and imaging.
- Further optimization is needed to balance targeting specificity with systemic distribution for improved therapeutic efficacy.
