Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections.
Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections.
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DOI：
10.1039/c8bm00282g
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发表时间：
2018-06-25
影响因子：
6.6
通讯作者：
Stayton PS
中科院分区：
文献类型：
--
作者：
Su FY ;Chen J ;Son HN ;Kelly AM ;Convertine AJ ;West TE ;Skerrett SJ ;Ratner DM ;Stayton PS
肺细胞内感染，如结核、炭疽和兔热病，仍然是常规抗生素治疗的重大挑战。这些感染的无效抗生素治疗不仅会导致不希望的副作用，而且还会出现抗生素耐药性。氨基糖苷类（例如，链霉素）长期以来一直是许多肺细胞内感染的治疗方案的一部分。然而，它们对细胞内细菌池的生物利用度受到膜渗透性差和快速消除的限制。为了应对这一挑战，开发了聚合物增强的脂质体（帕尔斯）以提供链霉素向肺泡巨噬细胞（细胞内病原体的重要宿主细胞）的改善的胞质递送。将多官能二嵌段共聚物工程化以用取代聚乙二醇化脂质组分的单一官能聚合物官能化具有碳水化合物介导的靶向、pH响应性药物释放和内体释放活性的PAL，以简化脂质体制剂。pH传感功能使帕尔斯能够在内体pH条件下提供链霉素的增强释放（6小时内70%释放），在生理pH 7.4下有限释放（16%）。在溶血试验中表征了与内体释放相关的膜去稳定化活性，帕尔斯在内体pH形成目标范围内显示出尖锐的pH曲线。在已建立的吡喃/对二甲苯二溴化双吡啶（DPX）荧光去猝灭测定中证明了这种膜去稳定pH曲线与模型药物释放的直接联系。帕尔斯显示出类似的急剧pH响应性释放，而PEG化的对照脂质体没有，并且随后显示出类似的链霉素释放曲线。帕尔斯的甘露糖靶向能力也被证明与非靶向PEG化脂质体相比具有2.5倍的内化。最后，与对照PEG化脂质体递送的游离链霉素或链霉素相比，负载链霉素的帕尔斯在弗朗西斯菌-巨噬细胞共培养模型中显示出显著改善的细胞内抗菌活性（分别为13倍和16倍）。这项研究表明，帕尔斯作为一个有用的平台，提供抗生素治疗细胞内巨噬细胞感染的潜力。一种简化的脂质体制剂，具有三种功能以增强抗生素对胞质细菌的生物利用度：碳水化合物介导的靶向; pH响应释放;内体释放活性。
Pulmonary intracellular infections, such as tuberculosis, anthrax, and tularemia, remain a significant challenge to conventionl antibiotic therapy. Ineffective antibiotic treatment of these infections can lead not only to undesired side effects, but also the emergence of antibiotic resistance. Aminoglycosides (e.g., streptomycin) have long been part of the therapeutic regiment for many pulmonary intracellular infections. Their bioavailability for intracellular bacterial pools, however, is limited by poor membrane permeability and rapid eliminaton. To address this challenge, polymer-augmented liposomes (PALs) were developed to provide improved cytosolic delivery of streptomycin to alveolar macrophages, an important host cell for intracellular pathogens. A multifunctional diblock copolymer was engineered to functionalize PALs with carbohydrate-mediated targeting, pH-responsive drug release, and endosomal release activity with a single functinoal polymer that replaces the pegylated lipid component to simplify the liposome formulation. The pH-sensing functionality enabled PALs to provide enhanced release of streptomycin under endosomal pH condition (70% release in 6 hours) with limited release at physiological pH 7.4 (16%). The membrane-destabilizing activity connected to endosomal release was characterized in a hemolysis assay and PALs displayed a sharp pH profile across the endosomal pH development target range. The direct connection of this membrane-destalizing pH profile to model drug release was demonstrated in an established pyranine / p-xylene bispyridinium dibromide (DPX) fluorescent dequenching assay. PALs displayed similar sharply pH-responsive release, whereas PEGylated control liposomes did not, and similar profiles were then shown for streptomycin release. The mannose-targeting capability of the PALs was also demonstrated with 2.5 times higher internalization compared to non-targeted PEGylated liposomes. Finally, the streptomycin-loaded PALs was shown with a significantly improved intracellular antibacterial activity in a Francisella-macrophage co-culture model, compared with free streptomycin or streptomycin delivered by control PEGylated liposomes (13× and 16×, respectively). This study suggests the potential of PALs as a useful platform to deliver antibiotics for the treatment of intracellular macrophage infections. A simplified liposome formulation with three functionalities to enhance antibiotic bioavailability to cytosolic bacteria: carbohydrate-mediated targeting; pH-responsive release; endosomal-releasing activity.
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DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
4.7
作者：
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通讯作者：
Futaki, Shiroh
影响因子：
5.5
作者：
KITANO, H;AKATSUKA, Y;ISE, N
通讯作者：
ISE, N
DOI：
10.1016/j.jconrel.2014.03.041
发表时间：
2014-10-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Keller S;Wilson JT;Patilea GI;Kern HB;Convertine AJ;Stayton PS
通讯作者：
Stayton PS
影响因子：
4.6
作者：
Lane DD;Su FY;Chiu DY;Srinivasan S;Wilson JT;Ratner DM;Stayton PS;Convertine AJ
通讯作者：
Convertine AJ