Di Venosa Gabriela M, Casas Adriana G, Battah Sinan, Dobbin Paul, Fukuda Haydée, Macrobert Alexander J, Batlle Alcira
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clinicas José de San Martin, University of Buenos Aires, Argentina.
Int J Biochem Cell Biol. 2006 Jan;38(1):82-91. doi: 10.1016/j.biocel.2005.08.001. Epub 2005 Sep 6.
Photodynamic therapy is a treatment for malignant and certain non-malignant lesions that involves administration of a photosensitising drug. The use of 5-aminolaevulinic acid-induced porphyrins has become one of the most active fields of photodynamic therapy research. Since the efficacy of the treatment is somewhat limited by the hydrophilic nature of 5-aminolaevulinic acid, chemical modifications such as esterification with aliphatic alcohols have been made to induce higher porphyrin production. In an attempt to improve delivery of 5-aminolaevulinic acid to tissue, we have investigated the use of dendritic derivatives capable of bearing several drug molecules. The aim of this work was to evaluate in vivo and in vitro the efficacy of the first generation dendron, aminomethane tris-methyl 5-aminolaevulinic acid (containing three 5-aminolaevulinic acid residues) in terms of porphyrin synthesis. In LM3 cells, the dendron induced similar porphyrin levels compared to equimolar concentrations of 5-aminolaevulinic acid. Although the dendron is taken up with comparable efficiency to 5-aminolaevulinic acid, we found that there is only partial intracellular liberation of 5-aminolaevulinic acid residues. Both systemic and topical administration of the dendron to tumour-bearing mice induced higher porphyrin levels than the widely investigated hexyl ester derivative in most tissues studied, although it was not possible to surpass the levels induced by 5-aminolaevulinic acid. In conclusion, aminomethane tris-methyl 5-aminolaevulinic acid is capable of being taken up by cells efficiently, and liberating the active residues, although in vivo it was not possible to improve upon the efficacy of 5-aminolevulinic acid. Studies of accessibility and regulation of the esterases are needed to improve the design of these dendritic derivatives.
光动力疗法是一种针对恶性和某些非恶性病变的治疗方法，该方法涉及给予一种光敏药物。利用5-氨基乙酰丙酸诱导产生卟啉已成为光动力疗法研究中最活跃的领域之一。由于5-氨基乙酰丙酸的亲水性在一定程度上限制了治疗效果，因此已进行了化学修饰，如用脂肪醇进行酯化，以诱导更高的卟啉生成量。为了提高5-氨基乙酰丙酸向组织的递送效率，我们研究了能够携带多个药物分子的树枝状衍生物的应用。这项工作的目的是在体内和体外评估第一代树枝状分子氨甲基三甲基5-氨基乙酰丙酸（含有三个5-氨基乙酰丙酸残基）在卟啉合成方面的疗效。在LM3细胞中，与等摩尔浓度的5-氨基乙酰丙酸相比，该树枝状分子诱导产生的卟啉水平相似。尽管该树枝状分子的摄取效率与5-氨基乙酰丙酸相当，但我们发现5-氨基乙酰丙酸残基在细胞内只有部分释放。对荷瘤小鼠进行树枝状分子的全身和局部给药后，在大多数研究组织中诱导产生的卟啉水平高于广泛研究的己酯衍生物，尽管无法超过5-氨基乙酰丙酸诱导的水平。总之，氨甲基三甲基5-氨基乙酰丙酸能够被细胞有效摄取并释放活性残基，尽管在体内无法提高5-氨基乙酰丙酸的疗效。需要对酯酶的可及性和调控进行研究，以改进这些树枝状衍生物的设计。
