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Designing Highly Stable Poly(sarcosine)-Based Telodendrimer Micelles with High Drug Content Exemplified with Fulvestrant
Macromolecules ( IF 5.1 ) Pub Date : 2022-01-07 , DOI: 10.1021/acs.macromol.1c02086 Qing Yu 1 , Richard M. England 1 , Anders Gunnarsson 2 , Robert Luxenhofer 3, 4 , Kevin Treacher 5 , Marianne B. Ashford 1
Macromolecules ( IF 5.1 ) Pub Date : 2022-01-07 , DOI: 10.1021/acs.macromol.1c02086 Qing Yu 1 , Richard M. England 1 , Anders Gunnarsson 2 , Robert Luxenhofer 3, 4 , Kevin Treacher 5 , Marianne B. Ashford 1
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Polymeric micelles have been extensively used as nanocarriers for the delivery of chemotherapeutic agents, aiming to improve their efficacy in cancer treatment. However, the poor loading capacity, premature drug release, non-uniformity, and reproducibility still remain the major challenges. To create a stable polymeric micelle with high drug loading, a telodendrimer micelle was developed as a nanocarrier for fulvestrant, as an example of a drug that has extremely poor water solubility (sub-nanomolar range). Telodendrimers were prepared by the synthesis of hydrophilic linear poly(sarcosine) and growing a lysine dendron from the chain terminal amine by divergent synthesis. At the periphery of the dendritic block, either 4, 8, or 16 fulvestrant molecules were conjugated to the lysine dendron creating a hydrophobic block. Having drug molecules as a part of the carrier not only reduces the usage of the inert carrier materials but also prevents the drugs from leakage and premature release by diffusion. The self-assembled telodendrimer micelles demonstrated good colloidal stability (cmc < 2 μM) in buffer and were uniform in size. In addition, these telodendrimer micelles could solubilize additional fulvestrant yielding an excellent overall drug loading capacity of up to 77 wt % total drug load (summation of conjugated and encapsulated). Importantly, the size of the micelles could be tuned between 25 and 150 nm by controlling (i) the ratio between hydrophilic and hydrophobic blocks and (ii) the amount of encapsulated fulvestrant. The versatility of these telodendrimer-based micelle systems to both conjugated and encapsulated drugs with high efficiency and stability, in addition to possessing other tuneable properties, makes it a promising drug delivery system for a range of active pharmaceutical ingredients and therapeutic targets.
中文翻译：
设计具有高药物含量的高度稳定的聚（肌氨酸）基末端树枝状聚合物胶束，以氟维司群为例
聚合物胶束已被广泛用作纳米载体，用于递送化学治疗剂，旨在提高其在癌症治疗中的功效。然而，负载能力差、药物释放过早、不均匀性和重现性仍然是主要挑战。为了制造具有高载药量的稳定聚合物胶束，开发了一种末端树枝状聚合物胶束作为氟维司群的纳米载体，作为水溶性极差（亚纳摩尔范围）的药物的一个例子。末端树枝状聚合物是通过合成亲水性线性聚（肌氨酸）并通过发散合成从链末端胺生长赖氨酸树突来制备的。在树枝状块的外围，4、8 或 16 个氟维司群分子与赖氨酸树枝结合，形成疏水块。将药物分子作为载体的一部分不仅减少了惰性载体材料的使用，而且还防止了药物泄漏和扩散过早释放。自组装的末端树枝状聚合物胶束在缓冲液中表现出良好的胶体稳定性（cmc < 2 μM）并且尺寸均匀。此外，这些末端树枝状聚合物胶束可以增溶额外的氟维司群，从而产生高达 77 wt% 总载药量（偶联和包封的总和）的优异总载药量。重要的是，通过控制 (i) 亲水性和疏水性嵌段之间的比率和 (ii) 包封氟维司群的量，胶束的大小可以在 25 和 150 nm 之间调整。这些基于末端树枝状大分子的胶束系统的多功能性对结合和包封药物具有高效和稳定性，
更新日期：2022-01-25
中文翻译：
设计具有高药物含量的高度稳定的聚（肌氨酸）基末端树枝状聚合物胶束，以氟维司群为例
聚合物胶束已被广泛用作纳米载体，用于递送化学治疗剂，旨在提高其在癌症治疗中的功效。然而，负载能力差、药物释放过早、不均匀性和重现性仍然是主要挑战。为了制造具有高载药量的稳定聚合物胶束，开发了一种末端树枝状聚合物胶束作为氟维司群的纳米载体，作为水溶性极差（亚纳摩尔范围）的药物的一个例子。末端树枝状聚合物是通过合成亲水性线性聚（肌氨酸）并通过发散合成从链末端胺生长赖氨酸树突来制备的。在树枝状块的外围，4、8 或 16 个氟维司群分子与赖氨酸树枝结合，形成疏水块。将药物分子作为载体的一部分不仅减少了惰性载体材料的使用，而且还防止了药物泄漏和扩散过早释放。自组装的末端树枝状聚合物胶束在缓冲液中表现出良好的胶体稳定性（cmc < 2 μM）并且尺寸均匀。此外，这些末端树枝状聚合物胶束可以增溶额外的氟维司群，从而产生高达 77 wt% 总载药量（偶联和包封的总和）的优异总载药量。重要的是，通过控制 (i) 亲水性和疏水性嵌段之间的比率和 (ii) 包封氟维司群的量，胶束的大小可以在 25 和 150 nm 之间调整。这些基于末端树枝状大分子的胶束系统的多功能性对结合和包封药物具有高效和稳定性，
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