Passive targeting of lipid-based nanoparticles to mouse cardiac ischemia–reperfusion injury
Summary (2 min read)
1. INTRODUCTION
- The best treatment option for acute myocardial infarction is currently early reperfusion of the affected myocardium.
- An emerging approach for further treatment of IR injury involves the delivery of therapeutic compounds to the myocardium to promote cell survival and constructively influence scar formation and myocardial remodeling (6,7).
- Furthermore, owing to their size, nanoparticles demonstrate prolonged retention in the infarct area, which is enabled by the presence of leaky vasculature (8,9).
- The authors studied micelles (diameter approximately 15 nm) and liposomes (diameter approximately 100 nm) to investigate influence of nanoparticle size.
- Furthermore, contrast-enhanced in vivo MRI was complemented with cine MRI to determine cardiac function.
2.1. Nanoparticle Characterization
- Micelles and liposomes were first characterized with respect to hydrodynamic size and MRI relaxivity properties at 1.41 and 9.4 T (Table 1).
- Micelle diameter was approximately 15 nm and the liposome diameter of 100 nm was significantly larger.
- At 1.41 T, the micelle and liposome longitudinal relaxivity (r1) values were higher than those for Gd–DTPA.
- Thus, the nanoparticles are powerful MRI contrast agents, which is further amplified by the high payload of Gd–DOTA-carrying lipids incorporated in the lipid membranes.
- The ratio of transversal and longitudinal relaxivities (r2/r1) of both micelles and liposomes was relatively high at 9.4 T, indicating that the nanoparticles will display a pronounced T2 shortening effect at high field strengths.
2.2. Blood Circulation Half-lives and Biodistribution
- To investigate the blood circulation half-lives and biodistribution, mice were injected with Gd–DTPA, micelles or liposomes and blood samples were obtained up to 48h after administration.
- Frommono-exponential fits the blood circulation half-lives were calculated (Fig. 1a).
- Previously, van Bochove et al. observed longer blood circulation half-lives in mice for micelles (22.5 2.8h) and liposomes (7.0 1.0h) containing neutral Gd–DTPA-carrying lipids (20).
- The large size of liposomes prohibits renal clearance and therefore it is likely that they are removed from the blood by the reticuloendothelial system.
- Myocardial IR injury resulted in a similar reduction in cardiac function at all investigated time points (Supporting Information, Fig. S1).
2.4. Acute IR Injury – Day 1
- For both groups the accumulation of Gd–DTPA and paramagnetic nanoparticles was visualized by T1-weighted short-axis multi-slice MRI at day 1 after the IR injury.
- In contrast to the observations for Gd–DTPA, administration of nanoparticles at day 1 resulted in hyperenhancement of remote cardiac tissue at 0.1h after injection, while the infarct area remained isointense and, therefore, appeared as a dark rim (Fig. 3a).
- Accumulation was high in the infarct border zones and in the core of the infarcted myocardium.
- For NIR visualization after staining, this laser intensity was always set to 50%.
- Liposomes had extravasated after 24 h of circulation and were massively associated with the infarcted myocardium, although the accumulation pattern appeared more scattered compared with micelles.
2.5. Chronic IR Injury – Weeks 1 and 2
- LGE MRI with Gd–DTPA resulted in hyperenhancement of chronic infarcts at 0.1 h after injection (Fig. 5a, c).
- Owing to fast washout, Gd–DTPA enhancement was absent at later time points.
- After short circulation of the nanoparticles (3 h), CLSM revealed diffuse accumulation of micelles in the infarcted myocardium, which sometimes co-localized with inflammatory cells (Figs 6 and 7).
2.6. Implications
- Micelles and particularly liposomes have extensively been studied and applied as drug carriers, mainly for oncological Figure 6.
- Autofluorescence is less intense in the infarcted myocardium.
- All images were obtained after 3h circulation of the nanoparticles.
- Cardiotoxicity, a well-known side effect of several cytotoxic anti-tumor drugs, for example, doxorubicin, can be diminished by encapsulation of the therapeutics (29,30).
- Importantly, in their study little to no accumulation of micelles and liposomes was observed in the healthy remote myocardium, indicating specific delivery of the nanoparticles to infarcted myocardium.
3. CONCLUSIONS
- In this study the extravasation and accumulation properties of paramagnetic micelles and liposomes in mouse myocardial IR injury were studied with MRI and CLSM.
- Micelles and liposomes accumulated massively and specifically in the acute infarcted myocardium.
- Micelles displayed faster accumulation kinetics compared with liposomes, presumably owing to their smaller size.
- Because the nanoparticles generated significant contrast in MRI they are suitable for combined imaging and therapy.
- Altogether, the authors conclude that the presented lipid-based nanoparticles are promising vehicles for drug targeting purposes in myocardial infarction.
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...The majority of clinically approved MRI contrast agents are based on paramagnetic gadolinium (Gd)-chelates, such as Gd-DTPA, Gd-DOTA and Gd-HPDO3A [DTPA, diethylenetriaminepentaacetic acid; DOTA, 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid; HPDO3A, 10-(2- hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid] (5)....
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References
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"Passive targeting of lipid-based na..." refers background in this paper
...The hyperenhancement slowly disappeared within the next 30min, in agreement with the extensively described LGE effect used to measure infarct size (24)....
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...Furthermore, accumulation of pegylated micelles in the infarcted myocardium has been demonstrated in a rabbit model of myocardial infarction (16)....
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...Therefore, micelles were proposed for delivery of lipophilic drugs (16,17)....
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