title: Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: High drug-loading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity.
abstract: As a sustained-release drug depot for localized cancer treatment, in situ thermo-sensitive hydrogel has attracted increasing interests. However, it is currently a big challenge to achieve high drug-loading, sustained and stable drug release, as well as long-term local drug retention simultaneously. We hypothesized that this goal could be accomplished by incorporating the nanocrystals (NCs) of a hydrophobic drug, such as paclitaxel (PTX) into the thermo-sensitive hydrogel (Gel). Hence, a PTX-NCs-Gel system has been constructed with thermo-sensitive Pluronic F127, using PTX-NCs and Taxol® as the controls. Besides, near infra-red agent DiR was used to prepare PTX/DiR hybrid NCs and PTX/DiR hybrid NCs-Gel as well. As a result, this hydrogel system could achieve a high drug loading of PTX up to 3 mg/ml while stabilize the particle size of PTX-NCs significantly compared with PTX-NCs alone. There was no obvious interaction between PTX-NCs and F127. Obviously, PTX/DiR hybrid NCs-Gel presented better localized retention capacity and a much longer retention time in murine 4T1 tumor than PTX/DiR hybrid NCs and Cremophor/ethanol solubilized DiR in vivo. With a linear elimination, over 10% of PTX still remained inside of mouse 4T1 tumor 20 days after intratumoral dosing of PTX-NCs-Gel. Importantly, PTX-NCs exhibited comparable cytotoxity against 4T1 and MCF-7 cells in vitro compared with Taxol®, which could ensure the efficacy of PTX-NCs-Gel. After intratumoral injection, PTX-NCs-Gel was found to be the most effective among all PTX formulations in the 4T1 and MCF-7 tumor-bearing mice models, with much lower system toxicity than Taxol®. In general, it is believed that the novel thermo-sensitive hydrogel system prepared in this study with PTX-NCs affords high drug-loading, sustained and stable drug release, as well as extended drug retention inside of tumor, which results in better therapy and lower toxicity.
authors: Zhiqiang
authors: Z
authors: Lin
authors: Wei
authors: W
authors: Gao
authors: Hongxiang
authors: H
authors: Hu
authors: Kun
authors: K
authors: Ma
authors: Bing
authors: B
authors: He
authors: Wenbing
authors: W
authors: Dai
authors: Xueqing
authors: X
authors: Wang
authors: Jiancheng
authors: J
authors: Wang
authors: Xuan
authors: X
authors: Zhang
authors: Qiang
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D006801:Humans; D020100:Hydrogels; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D013696:Temperature; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D020100:Hydrogels; D017239:Paclitaxel