Photosensitizer delivery to vulnerable atherosclerotic plaque: comparison of macrophage-targeted conjugate versus free chlorine(e6)

Abstract

We have previously shown that a conjugate (MA-ce6) between maleylated serum albumin and the photosensitizer chlorin(e6) (ce6) is targeted in vitro to macrophages via class A scavenger receptors. We now report on the ability of this conjugate to localize in macrophage-rich atherosclerotic plaques in vivo. Both the conjugate and the free photosensitizer ce6 are studied after injection into New Zealand White rabbits that are rendered atherosclerotic by a combination of aortic endothelial injury and cholesterol feeding into normal rabbits. Rabbits are sacrificed at 6 and 24 h after injection and intravascular fluorescence spectroscopy is carried out by fiber-based fluorimetry in intact bloodfilled arteries. Surface spectrofluorimetry of numbered excised aortic segments together with injured and normal iliac arteries is carried out, and quantified ce6 content by subsequent extraction and quantitative fluorescence determination of the arterial segments and also of nontarget organs. There is good agreement between the various techniques for quantifying ce6 localization, and high contrast between arteries from atherosclerotic and normal rabbits is obtained. Fluorescence correlates with the highest burden of plaque in the aorta and the injured iliac artery. The highest accumulation in plaques is obtained using MA-ce6 at 24 h. Free ce6 gives better accumulation at 6 h compared to 24 h. The liver, spleen, lung, and gall bladder have the highest uptake in nontarget organs. Macrophagetargeted photosensitizer conjugates may have applications in both detecting and treating inflamed vulnerable plaque.

Optical molecular imaging in atherosclerosis

“…Accordingly, the probe was shown to be potentially useful for measurement of plaque inflammation. 24,25 a v b 3 integrins which are receptors which help in cell-cell and cell-matrix binding and important part of cell signaling cascade. These receptors are highly expressed by macrophages in plaque lesions and play a key role on pathogenesis of atherosclerosis.…”

“…Such photodynamic activity can allow for both diagnosis and therapy with a single optical imaging system. 25 Before optical imaging methods could be used clinically, the technology will need to be further developed along two major fronts. First, the optical imaging agents will need to undergo substantial development and testing before use in patients; prior clinical experience with indocyanine green (ICG), an NIR fluorochrome, suggests that organic fluorochromes will be well tolerated with a low adverse event rate.…”

The impact of macrophage-cancer cell interaction on the efficacy of photodynamic therapy

“…46 The strategy of macrophage-targeting by scavenger-receptor targeted conjugates was later utilized to localize photosensitizers to vulnerable atherosclerotic plaques in rabbits, allowing fluorescence diagnosis and PDT; these lesions are particularly rich in macrophages. 47,48 Macrophage-targeted photosensitizer delivery for both diagnostic and therapeutic purposes can be facilitated by the nanoparticles technology. The nanoformulations explored for such approach include: biodegradable polymer poly(DL-lactide-co-glycolide) containing photosensitizer bacteriochlorophyll- a 49 , theranostic nanoparticles prepared by conjugating photosensitizer chlorin e6 to hyaluronic acid 50 , and positively charged nanoparticles consisting of a calcium phosphate core with shells of carboxymethyl cellulose and poly(ethyleneimine) loaded with photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)-porphyrin (mTHPP) 51 .…”

Nanotechnology for photodynamic therapy: a perspective from the Laboratory of Dr. Michael R. Hamblin in the Wellman Center for Photomedicine at Massachusetts General Hospital and Harvard Medical School

“…This tumor macrophage work led to several publications [31-33]. The atherosclerosis work also led to several publications [34, 35]. …”

“…Hamblin expanded on his original discovery of polycationic photosensitizer conjugates [34-40] to start a broad-ranging research program in antimicrobial PDT that has led to the Hamblin Laboratory becoming a world leader in this field [41-44]. In 2001, Dr. Hamblin was awarded a NIH grant entitled “Photodynamic Therapy for Localized Infections,” which has been continuously funded up to the present day and is now funded until 2018.…”