Information-Based Design of Polymeric Drug Formulation Additives,Biomacromolecules

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Information-Based Design of Polymeric Drug Formulation Additives
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-11-23 , DOI: 10.1021/acs.biomac.0c01284
Sandra Arias ₁ , Eva Maron ₁ , Hans G Börner ₁

Affiliation

Tailor-made copolymers are designed based on a peptide-poly(ethylene glycol) (QFFLFFQ-PEG) conjugate as a blueprint, to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC). The relevant functionalities of the parent peptide-PEG are mimicked by employing monomer pairs that copolymerize in a strictly alternating manner. While styrene (S) or 4-vinylbenzyl-phthalimide (VBP) provide aromatic moieties like Phe, the aliphatic isobutyl side chain of Leu4 is mimicked by maleic anhydride (MA) that reacts after polymerization with isobutylamine to give the isobutylamide-carboxyl functional unit (iBuMA). A set of copolymer-PEG solubilizers is synthesized by controlled radical polymerization, systematically altering the length of the functional segment (DP_n = 2, 4, 6) and the side chain functionalization (iBuMA, iPrMA, MeMA). The m-THPC hosting and release properties of P[S-alt-iBuMA]₆-PEG reached higher payload capacities and more favored release rates than the parent peptide-PEG conjugate. Interestingly, P[S-alt-RMA]_n-PEG mimics the sensitivity of the peptide-PEG solubilizer well, where the exchange of Leu4 residue by Val and Ala significantly reduces the drug loading by 92%. A similar trend is found with P[S-alt-RMA]_n-PEG as the exchange of iBu → iPr → Me reduces the payload capacity up to 78%.

中文翻译：

基于信息的高分子药物制剂添加剂设计

基于肽-聚（乙二醇）（QFFLFFQ-PEG）共轭物设计蓝图量身定制的共聚物，以增溶光敏剂间-四（羟苯基）二氢卟酚（m -THPC）。通过使用以严格交替的方式共聚的单体对来模仿母体肽-PEG的相关功能。苯乙烯（S）或4-乙烯基苄基邻苯二甲酰亚胺（VBP）提供芳族部分（如Phe），Leu4的脂肪族异丁基侧链被马来酸酐（MA）模仿，后者在与异丁胺聚合后发生反应，得到异丁酰胺-羧基官能团（ iBuMA）。通过受控的自由基聚合反应，可以系统地改变功能段的长度（DP _n= 2，4，6）和侧链功能化（iBuMA，iPrMA，MeMA）。与母体肽-PEG共轭物相比，P [S- alt- iBuMA] ₆ -PEG的m -THPC宿主和释放特性达到了更高的有效负载能力和更有利的释放速率。有趣的是，P [S- alt- RMA] _n -PEG很好地模拟了肽-PEG增溶剂的敏感性，其中Val和Ala交换Leu4残基显着降低了92％的载药量。在P [S -alt- RMA] _n -PEG中也发现了类似的趋势，因为iBu→iPr→Me的交换将有效负载容量降低了78％。

更新日期：2021-01-11

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