<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel&ndash;cholesterol complexes</p>

Abstract

Background: Keloids represent benign fibroproliferative tumors which result from elevated expression of inflammation. Paclitaxel (PTX) was an effective chemotherapeutic agent and has been reported to have anti-fibrotic effects, but the strong hydrophobicity brings a challenge for its clinical application. Purpose: The objective of this study was to improve the water solubility of PTX and investigate its anti-keloid effects. Methods: We prepared a PTX-cholesterol-loaded liposomes (PTXL) by thin film evaporation fashion and characterized their physicochemical properties. We also investigated the effects of PTX on proliferation, invasion and fibrosis of keloid fibroblasts in vitro and in vivo. Results: The prepared PTXL have a spherical appearance, a particle size of 101.43 nm and a zeta potential of-41.63 mV. PTXL possessed a high drug entrapment efficiency of 95.63% and exhibited a good stability within 30 days. The drugs in PTXL were released in a slow and sustained mode. The PTXL could be effectively uptaken into human keloids fibroblast (HKFs) in a time-dependent manner. In vitro, PTXL showed better ability on inhibiting cell proliferation, migration and invasion, and effectively on promoting apoptosis and arresting cell cycle in G 2 /M phase compared to PTX. Meanwhile, in vivo studies indicated that the PTXL had better performance on inhibiting the keloids growth compared to the PTX in keloid-bearing BALB/c nude mice model. Finally, we found PTX treatment suppressed the production of tumor necrosis factor alpah (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta (TGF-β) and inhibited the expression of alpha smooth muscle actin (α-SMA) and collagen I in HKFs. The activation of protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) signaling pathway also blocked by PTX in cultured HKFs and keloid tissues. LY294002, a PI3K (phosphatidylinositol 3-kinase)/AKT inhibitor, also suppressed the expression of TNF-α, IL-6 and TGF-β, and simultaneously, reduced the production of α-SMA and collagen I in HKFs. The inhibition of AKT/GSK3β signaling pathway contribute to inhibit the generation of fibrogenic cytokines by PTXL on ameliorating fibrosis progress in keloids. Conclusion: Our results suggested that the developed PTXL would become a promising therapeutic agent in the field of anti-keloid therapy.

The Roles of Inflammation in Keloid and Hypertrophic Scars

“…By using keloid-bearing nude mice model, Wang et al demonstrated PTX had inhibitory effect on keloids growth (63). In vitro, the authors were able to show that the expression of IL-6 and TNF-a, as well as the production of a-SMA and collagen I, by human keloids fibroblast decreased after paclitaxel administration (63). This is consistent with the conclusion drawn on a rabbit ear hypertrophic scar model.…”

“…This anti-inflammatory and anti-fibrosis effect was also observed in animal models of keloid (63) and hypertrophic scar (64). By using keloid-bearing nude mice model, Wang et al demonstrated PTX had inhibitory effect on keloids growth (63). In vitro, the authors were able to show that the expression of IL-6 and TNF-a, as well as the production of a-SMA and collagen I, by human keloids fibroblast decreased after paclitaxel administration (63).…”

“…For instance, PTX was found to inhibit NF-kB pathway (61) and attenuate interstitial fibrosis in mice kidneys by blocking STAT-3 signaling (62). This anti-inflammatory and anti-fibrosis effect was also observed in animal models of keloid (63) and hypertrophic scar (64). By using keloid-bearing nude mice model, Wang et al demonstrated PTX had inhibitory effect on keloids growth (63).…”

The Efficacy of Cholesterol-Based Carriers in Drug Delivery

“…In vitro drug release showed a sustained release of PTX from PTXL. Cellular uptake studies showed that PTXL were partially taken up by human keloid fibroblasts (HKFs) through caveolin-mediated endocytosis rather than clathrin [ 140 ]. PTXL inhibited cell proliferation better than PTX when tested at the same concentration range of 0.05–10 µg/mL.…”

“…PTXL inhibited the AKT/GSK3β signaling pathway, thus reducing the production of fibrogenic cytokines such as IL-6, TNF-α and TGF-β, which consequently ameliorated fibrosis progress in keloids. The results showed the potential of PTXL in treating keloids [ 140 ].…”