A POLYMER TRITON X-100 CONJUGATE CAPABLE OF PH-DEPENDENT RED-BLOOD-CELL LYSIS - A MODEL SYSTEM ILLUSTRATING THE POSSIBILITY OF DRUG-DELIVERY WITHIN ACIDIC INTRACELLULAR COMPARTMENTS
A POLYMER TRITON X-100 CONJUGATE CAPABLE OF PH-DEPENDENT RED-BLOOD-CELL LYSIS - A MODEL SYSTEM ILLUSTRATING THE POSSIBILITY OF DRUG-DELIVERY WITHIN ACIDIC INTRACELLULAR COMPARTMENTS
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DOI：
10.3109/10611869409015915
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发表时间：
1994-01-01
影响因子：
4.5
通讯作者：
BIGNOTTI, F
中科院分区：
文献类型：
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作者：
DUNCAN, R;FERRUTI, P;BIGNOTTI, F
聚酰胺基胺是含有叔氨基和沿大分子链规则排列的酰胺基团的可溶性聚合物，随着pH从中性变为酸性，其净平均电荷发生显着变化，导致构象发生变化。这一特性提供了设计聚合物-药物缀合物的可能性，该缀合物在静脉内给药后相对紧凑，从而保护循环中的药物有效负载，但在胞饮内化到酸性细胞内区室后展开，允许pH触发的细胞内药物递送。为了研究该方法的可行性，制备了包含膜溶解非离子去污剂Triton X-100（作为模型）的聚酰胺胺（MBI）共价缀合物，并以其体外裂解红细胞的能力作为不同pH下缀合物构象的指示剂。尽管 Triton X-100 在 pH 5.5、7.4 和 8.0 下具有高度溶解性，并且母体聚合物 MBI 在任何条件下均不溶解，但该缀合物仅在 pH 5.5 下表现出浓度依赖性红细胞溶解。此外，人类白血病细胞 (CCRF) 与这些底物的孵育显示，缀合物比 MBI 毒性更大（IC50 值分别为 100 μg/ml 和 650 μg/ml），并且比 Triton X-100 毒性更低（IC50 为 1 μg/ml）。
Poly(amidoamines) are soluble polymers containing tertiary amino and amido groups regularly arranged along the macromolecular chain, and their net average charge alters considerably as pH changes from neutral to acidic leading to a change in conformation. This property provides the possi bility to design polymer-drug conjugates that are, following intravenous administration, relatively compacted and thus protect a drug payload in the circulation, but following pinocytic internalisation into acidic intracellular compartments unfold permitting pH-triggered intracellular drug delivery. To study the feasibility of this approach, a covalent conjugate of a poly(amidoamine) (MBI) was prepared to contain the membrane lytic non-ionic detergent Triton X-100 (as a model), and its ability to lyse red blood cells in vitro was used as an indicator of conjugate conformation at different pHs. Although Triton X-100 was highly lytic at pH 5.5, 7.4 and 8.0, and the parent polymer MBI was not lytic under any conditions, the conjugate only showed concentration-dependent red blood cell lysis at pH 5.5. Moreover, incubation of human leukaemic cells (CCRF) with these substrates showed conjugate to be more toxic than MBI (IC50 values of 100 mu g/ml and 650 mu g/ml respectively) and less toxic than Triton X-100 (IC50 of 1 mu g/ml).