PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2024
·
IF 2.6
Yun Meng,Ye Cai,Mengyao Cui,Yuhang Xu,Long Wu,Xiang Li,Xiaoqin Chu
The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.
研究领域:
药剂学
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药物递送系统
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药代动力学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Na Li,Yunjian Yu,Qixian Chen,Jiazhen Niu,Chan Gao,Xiongwei Qu,Jimin Zhang,Hui Gao
ABSTRACT Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum ( F. nucleatum ) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum -associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3′-diaminodipropylamine-pendant poly(β-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum -colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum -resident CRC. Statement of Significance Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum . To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum -associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum -resident CRC.
研究领域:
癌症生物学
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分子生物学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 87
·84164-84176
·
IF 3.289
Huipeng Li,Nida El Islem Guissi,Zhigui Su,Qineng Ping,Minjie Sun
Nano-structured lipid carriers (NLCs) have been widely used for oral drug delivery due to their remarkable biocompatibility and biodegradability. In addition to formulation and particle size, particle surface properties are important for overcoming gastrointestinal (GI) barriers to oral drug delivery by lipid-based nanoparticles. In this study, we describe polyethylene glycol (PEG)-based mucus-penetrating NLCs and we report the effect of surface hydrophilic properties on their oral delivery across the GI mucus and intestinal epithelium cells in vivo and in vitro. The solvent evaporation method was used to prepare PEG-modified NLCs (pNLCs) with three different levels of polyethylene glycol (100) monostearate (S100) as the hydrophilic coating material. The stability and cytotoxicity of pNLCs, as well as their uptake by Caco-2 cells and transport across Caco-2 monolayers and mucus-secreting Caco-2/HT29 coculture monolayers, were investigated to confirm the optimal PEG level for oral delivery. In situ single-pass perfusion experiments, in vivo imaging and in vivo oral pharmacokinetic studies were also performed in rodents to evaluate the oral absorption of pNLCs with different hydrophilic surface properties. Our results showed that the hydration layer thickness of the pNLCs increased with the increasing S100 content. NLC containing 20% S100 (pNLC-20%) showed the highest uptake by Caco-2 cells and the most effective permeation through Caco-2/HT29 coculture monolayers compared with unmodified NLC, pNLC-40% and pNLC-80%. In addition, pNLC-20% was the most stable during the process of oral administration and uptake into the blood circulation, as judged by fluorescence resonance energy transfer (FRET). Moreover, in situ single-pass perfusion experiments, ligated intestinal loops tests, in vivo imaging and pharmacokinetics studies also demonstrated that pNLC-20% most rapidly penetrated the intestinal epithelium and had the highest AUC and Cmax of all the NLCs. In conclusion, optimization of surface hydrophilic properties is essential for enhancing the absorption of drugs delivered by oral administration of lipid-based nanocarriers.
研究领域:
药剂学
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纳米技术
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2011
·
IF 7.883
Yun Jin,Yupin Song,Xi Zhu,Dan Zhou,Chunhui Chen,Zhirong Zhang,Yuan Huang
The present study was to demonstrate the effects of goblet cell-targeting nanoparticles on the oral absorption of insulin in vitro , ex vivo and in vivo , and identify the targeting mechanism as well as the influence of mucus. The insulin loaded nanoparticles were prepared using trimethyl chitosan chloride (TMC) modified with a CSKSSDYQC (CSK) targeting peptide. Compared with unmodified nanoparticles, the CSK peptide modification could facilitate the uptake of nanoparticles in villi, enhance the permeation of drugs across the epithelium, meanwhile, induce a significantly higher internalization of drugs via clathrin and caveolae mediated endocytosis on goblet cell-like HT29-MTX cells. In transport studies across Caco-2/HT29-MTX co-cultured cell monolayer (simulating intestinal epithelium), the CSK peptide modification also showed enhanced transport ability, even if the targeting recognition was partially affected by mucus. Moreover, it was found the existence of mucus was propitious to the transport of insulin from both modified and unmodified nanoparticles. In the pharmacological and pharmacokinetic studies in diabetic rats, the orally administrated CSK peptide modified nanoparticles produced a better hypoglycemic effect with a 1.5-fold higher relative bioavailability compared with unmodified ones. In conclusion, CSK peptide modified TMC nanoparticles showed sufficient effectiveness as goblet cell-targeting nanocarriers for oral delivery of insulin.
研究领域:
药学科学
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纳米技术
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药物递送系统
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糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）