Biopharmaceutics of boronated radiosensitizers: liposomal formulation of MnBOPP (manganese chelate of 2,4-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX) and comparative toxicity in mice.
Biopharmaceutics of boronated radiosensitizers: liposomal formulation of MnBOPP (manganese chelate of 2,4-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX) and comparative toxicity in mice.
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硼化放射增敏剂的生物药剂学：MnBOPP（2,4-（α，β-二羟乙基）氘卟啉 IX 的锰螯合物）的脂质体制剂和小鼠中的比较毒性。
DOI：
10.1021/js980454i
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Straubinger,RM
中科院分区：
文献类型：
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作者：
Zhou,R;Balasubramanian,SV;Kahl,SB;Straubinger,RM
二元治疗模式，如光动力学治疗（PDT）和中子捕获治疗（NCT），将联合收割机低毒性电磁辐射与适当的辐射增敏剂相结合，以增强对肿瘤靶点的选择性。2，4-（α，β-二羟乙基）脱氧卟啉IX（BOPP）的卟啉衍生物四碳硼烷羧酸酯显示肿瘤选择性摄取，并在两种治疗方式中具有活性。BOPP还螯合顺磁性离子，如Mn 2+，因此其组织积累和选择性可以通过使用磁共振成像非侵入性地检测。然而，Mn 2+螯合物（MnBOPP）的局部和全身毒性似乎升高，但表征不佳。在这里，我们开发了MnBOPP的脂质体制剂，并将其毒性与在盐水中给予小鼠的MnBOPP的毒性进行了比较。通过差示扫描量热法和包封率研究了最佳脂质体组成和容纳MnBOPP的最大容量。MnBOPP定量封装在不同组合物的脂质体中高达12摩尔%（药物：脂质），并在延长透析期间保持掺入。在高于12%药物时观察到药物和脂质富集区域的相分离。缓冲盐水中的MnBOPP在90 µmol/kg时对动物是致命的，在60 µmol/kg或更高剂量水平时在注射部位引起严重坏死。相比之下，在脂质体中配制的MnBOPP在135 μmol/kg的最高测试剂量下耐受良好，消除了局部毒性。
Binary treatment modalities such as photodynamic therapy (PDT) and neutron capture therapy (NCT) combine low‐toxicity electromagnetic irradiation with an appropriate radiation sensitizer to enhance selectivity for tumor targets. The porphyrin derivative tetrakiscarborane carboxylate ester of 2,4‐(α,β‐dihydroxyethyl) deu‐terioporphyrin IX (BOPP) shows tumor‐selective uptake and is active in both treatment modalities. BOPP also chelates paramagnetic ions such as Mn2+, and therefore its tissue accumulation and selectivity can be detected noninvasively by using magnetic resonance imaging. However, local and systemic toxicity appears elevated for the Mn2+chelate (MnBOPP), but is poorly characterized. Here we have developed a liposomal formulation of MnBOPP and compared its toxicity with that of MnBOPP administered to mice in saline. The optimal liposome composition and maximal capacity to accommodate MnBOPP were investigated by differential scanning calorimetry and by encapsulation efficiency. MnBOPP was encapsulated quantitatively at up to 12 mol % (drug:lipid) in liposomes of varying composition, and remained incorporated during extended dialysis. Phase separation of drug‐ and lipid‐rich domains was observed above 12% drug. MnBOPP in buffered saline was lethal to animals at 90 µmol/kg, and caused severe necrosis at the injection site at dose levels of 60 µmol/kg or greater. In contrast, MnBOPP formulated in liposomes was well tolerated at the highest tested dose of 135 µmol/kg, with the elimination of local toxicity.