Department of Pharmaceutics, College of Pharmacy, Kuwait University, Safat, 13110, Kuwait.
Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Int J Nanomedicine. 2024 Apr 29;19:3861-3890. doi: 10.2147/IJN.S445955. eCollection 2024.
Cystic fibrosis (CF) is associated with pulmonary infections persistent to antibiotics.
To eradicate biofilms, solid lipid nanoparticles (SLNs) loaded with quorum-sensing-inhibitor (QSI, disrupting bacterial crosstalk), coated with chitosan (CS, improving internalization) and immobilized with alginate lyase (AL, destroying alginate biofilms) were developed.
SLNs (140-205 nm) showed prolonged release of QSI with no sign of acute toxicity to A549 and Calu-3 cells. The CS coating improved uptake, whereas immobilized-AL ensured >1.5-fold higher uptake and doubled SLN diffusion across the artificial biofilm sputum model. Respirable microparticles comprising SLNs in carbohydrate matrix elicited aerodynamic diameters MMAD (3.54, 2.48 µm) and fine-particle-fraction FPF (65, 48%) for anionic and cationic SLNs, respectively. The antimicrobial and/or antibiofilm activity of SLNs was explored in reference mucoid/nonmucoid strains as well as clinical isolates. The full growth inhibition of planktonic bacteria was dependent on SLN type, concentration, growth medium, and strain. OD measurements and live/dead staining proved that anionic SLNs efficiently ceased biofilm formation and eradicated established biofilms, whereas cationic SLNs unexpectedly promoted biofilm progression. AL immobilization increased biofilm vulnerability; instead, CS coating increased biofilm formation confirmed by 3D-time lapse confocal imaging. Incubation of SLNs with mature biofilms of isolates increased biofilm density by an average of 1.5-fold. CLSM further confirmed the binding and uptake of the labeled SLNs in biofilms. Considerable uptake of CS-coated SLNs in non-mucoid strains could be observed presumably due to interaction of chitosan with LPS glycolipids in the outer cell membrane of .
The biofilm-destructive potential of QSI/SLNs/AL inhalation is promising for site-specific biofilm-targeted interventional CF therapy. Nevertheless, the intrinsic/extrinsic fundamentals of nanocarrier-biofilm interactions require further investigation.
囊性纤维化（CF）与对抗生素持续存在的肺部感染有关。
为了消除生物膜，开发了负载群体感应抑制剂（QSI，破坏细菌串扰）的固体脂质纳米粒（SLN），用壳聚糖（CS，提高内化）包被，并固定用藻酸盐裂解酶（AL，破坏藻酸盐生物膜）。
SLN（140-205nm）表现出 QSI 的延长释放，对 A549 和 Calu-3 细胞没有急性毒性的迹象。CS 涂层提高了摄取，而固定化 AL 确保了摄取增加了>1.5 倍，并且使 SLN 在人工生物膜痰模型中的扩散增加了一倍。包含 SLN 的碳水化合物基质中的可呼吸微粒引起空气动力学直径 MMAD（3.54、2.48μm）和细颗粒分数 FPF（阴离子和阳离子 SLN 分别为 65、48%）。在参考粘液/非粘液株以及临床分离株中研究了 SLN 的抗菌和/或抗生物膜活性。浮游细菌的完全生长抑制取决于 SLN 类型、浓度、生长培养基和菌株。OD 测量和死活染色证明阴离子 SLN 有效地停止生物膜形成并根除已建立的生物膜，而阳离子 SLN 出人意料地促进了生物膜的进展。AL 固定化增加了生物膜的脆弱性；相反，CS 涂层增加了生物膜形成，这通过 3D 延时共聚焦成像得到了证实。用分离株的成熟生物膜孵育 SLN 会使生物膜密度平均增加 1.5 倍。CLSM 进一步证实了标记的 SLN 在生物膜中的结合和摄取。在非粘液株中可以观察到 CS 涂层的 SLN 的大量摄取，推测是由于壳聚糖与外细胞膜中的 LPS 糖脂相互作用所致。
QSI/SLN/AL 吸入的生物膜破坏性潜力有望成为针对特定部位的生物膜靶向 CF 治疗的介入治疗。然而，纳米载体-生物膜相互作用的内在/外在基础仍需要进一步研究。
