Tracing Boron with Fluorescence and Positron Emission Tomography Imaging of Boronated Porphyrin Nanocomplex for Imaging-Guided Boron Neutron Capture Therapy

Abstract

Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible poly(lactide-co-glycolide)−monomethoxy-poly(polyethylene-glycol) (PLGA−mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with the previously reported boronated porphyrin drugs. Fluorescence imaging and positron emission tomography (PET) imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17 ± 13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumors to liver, muscle, fat, and blood were 3. 24 ± 0.22, 61.46 ± 20.26, 31.55 ± 10.30, and 33.85 ± 5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT.

Boron neutron capture therapy: Current status and future perspectives

“…The stable boron delivery agents with low and high molecular weight connected with a tumor-targeting component or moiety via a hydrolytically stable linkage (boron carriers) belong to this group of compounds ( Figure 2). In particular, these thirdgeneration boron compounds include boronated DNA intercalators [30], boronated amino acids [31], boronated lipopeptides [32], boronated peptides [33], boronated folate receptor [34], boronated epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) [35], boron-containing immunoliposomes [36] and liposomes [37,38], BSH-loaded polymeric micelles [39], transferrin-polyethylene glycol liposomes [40], maleimide-functionalized closo-dodecaborate albumin conjugates [41], carboranyl nucleosides [42], boronated porphyrins [43], boron-containing nanoparticles [44] coupled with cationic microbubble-assisted focused ultrasound (MB+FUS) treatment [45], pentanuclear porphyrazine complexes [46], boronated cyclic peptides [47], and boron nitride nanotubes [48].…”

“…Promising results have been achieved using electroporation as well as FUS treatment and pulsed high-intensity focused ultrasound (HIFU) as methods for the delivery of boronated compounds to tumor cells [43]. It has been shown that electroporation can significantly increase the absolute and relative tumor boron concentrations and assist in optimizing the qualitative micro distribution of boron, as well as the retention of boron in vitro and in vivo, for different tumor cells [49,50].…”

“…One of the problems that nuclear doctors face when using neutron irradiation is the lack of a quantitative imaging method for evaluation of the boron concentration. To solve this problem and to achieve selective tumor accumulation and reduced toxicity, several approaches have been applied: (1) coating of boronated porphyrins with biocompatible poly(lactide-co-glycolide)monomethoxypoly(polyethylene-glycol) (PLGA-mPEG) micelles [43], functionalizing mesoporous silica nanoparticles [51], labeling MMT1242 with a nitrobenzoxadiazole frame, which emits green-yellow fluorescence [52], and so on, in general, labeling vesicles by different fluorophores or molecules with fluorescence properties [53,54]. Ion microscopy may also be used to evaluate the distribution of isotope 10 B, as was shown in two brain tumor models, the 9L rat gliosarcoma and the F98 rat glioma [55].…”

Development history of boron delivery agents

“…性更强、降解性能更好, 也是一种很有用途的胶束药 物载体 [201,202] . Shi等 [89] 使用甲氧基-聚乙二醇-聚丙交 的结构 [166] ; (c) Na 3 [a 2 -B 20 H 17 NH 2 CH 2 -CH 2 NH 2 ]的结构 [167] ; (d) 脂质体脂内封装MAC同时囊内封装 TAC示意图 [169] (网络版彩图)…”

“…为3.12, 肿瘤内滞留时间超过48 h. SWCNT还具备荧光 成像性能 [212] . Yamagami等 [213] [199] ; (b) BPN示意图 [89] ; (c) Pcy示意图 [203] ; (d) MPEG-b-P(LA-co-D-Gal-MPCB)示意图 [204] (网络版彩图) . 在纳米医学的研究基础上, 含硼 量丰富(约50%)的氮化硼纳米材料是非常有潜力的纳…”