Departments of Chemistry, Chemical Engineering, and Materials Science and Engineering, ‡Laboratory for Synthetic-Biologic Interactions, and §Texas A&M Institute for Preclinical Studies, Texas A&M University , College Station, Texas 77842, United States.
J Am Chem Soc. 2015 Feb 11;137(5):2056-66. doi: 10.1021/ja512616s. Epub 2015 Jan 28.
Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 μg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.
纳米材料具有通过局部持续释放高浓度治疗剂来提供有效治疗毁灭性疾病的巨大潜力，尤其是当给药途径允许直接进入病变组织时。已经从两亲嵌段接枝三嵌段共聚物，PEBP-b-PBYP-g-PEG 设计了可生物降解的多磷酸酯基聚合物胶束和壳交联 knedel 样纳米颗粒（SCKs），它们可以有效地掺入高浓度的紫杉醇（PTX）。制备了物理负载紫杉醇的良好分散纳米颗粒，表现出理想的物理化学特性。将 10wt%的 PTX 包封到胶束或 SCK 中，可以使 PTX 在水中的浓度达到 4.8mg/mL 的悬浮液，而药物单独在水中的溶解度小于 2.0μg/mL。药物释放研究表明，这些纳米结构中释放的 PTX 通过结构-功能关系来定义，其中通过交联胶束结构形成 SCK 使持续释放 PTX 的半衰期增加一倍。体外，物理负载的胶束和 SCK 纳米药物对已知转移到肺部的骨肉瘤细胞系（CCH-OS-O 和 SJSA）表现出 IC50 值，与药物 Taxol 制剂相似。体内评估这些材料提供了对纳米颗粒结构-功能关系对气管内给药及其相关生物分布和药代动力学的影响的理解。总的来说，我们已经证明了这些新型纳米药物在通过直接施用于骨肉瘤肺转移部位来进行未来的持续释放治疗方面的潜力。
