Docetaxel-Loaded Cholesterol-PEG Co-Modified Poly (n-Butyl) Cyanoacrylate Nanoparticles for Antitumor Drug Pulmonary Delivery: Preparation, Characterization, and in vivo Evaluation

Int J Nanomedicine. 2020 Jul 28:15:5361-5376. doi: 10.2147/IJN.S249511. eCollection 2020.

Abstract

Background and aim: Polymeric nanoparticles (NPs) have received much attention as promising carrier systems in lung cancer and brain metastases.

Methods: Here, for the first time, we investigated the feasibility of using inhaled cholesterol-PEG co-modified poly (n-butyl) cyanoacrylate NPs (CLS-PEG NPs) of docetaxel (DTX) for sustained pulmonary drug delivery in cancer metastasis.

Results: Spray-dried or freeze-dried NPs yielded sustained drug release in vitro. In vitro inhalation evaluation data indicated that the inhalation formulation had better inhalability. Compared with intravenous (IV) administration, pharmacokinetic data suggested that the inhalation formulation prolonged plasma concentration of DTX for greater than 24 h and is more quickly and completely absorbed into the rat lung after intratracheal (IT) administration. Furthermore, freeze-dried powders were found to increase the t1/2 and area under curve (AUC) by 2.3 and 6.5 fold compared to the free drug after IT administration, and spray-dried powders were found to increase the t1/2 and AUC by 3.4 and 8.8 fold, respectively. After pulmonary administration of the inhalation formulation, DTX appeared to prolong the pulmonary absorption time. In addition, the inhalation formulation was distributed to the brain in a sustained release manner.

Conclusion: These experimental results demonstrated that freeze- and spray-dried powders have the potential for pulmonary sustained release, and they also have the potential to be used as a novel treatment for the delivery of drugs that pass through the air-blood barrier and enter the brain and are efficient carriers for the treatment of brain metastasis.

Keywords: docetaxel; dry powder; lung cancer; pulmonary delivery; spray-drying.

MeSH terms

  • A549 Cells
  • Administration, Inhalation
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Brain / drug effects
  • Cholesterol / chemistry
  • Delayed-Action Preparations
  • Docetaxel / administration & dosage*
  • Docetaxel / pharmacokinetics
  • Drug Carriers / administration & dosage
  • Drug Delivery Systems / methods
  • Enbucrilate / chemistry
  • Female
  • Freeze Drying
  • Humans
  • Lung / drug effects
  • Lung Neoplasms / drug therapy*
  • Male
  • Mice, Inbred C57BL
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Particle Size
  • Polymers / chemistry
  • Powders / chemistry
  • Rats, Wistar
  • Tissue Distribution

Substances

  • Antineoplastic Agents
  • Delayed-Action Preparations
  • Drug Carriers
  • Polymers
  • Powders
  • Docetaxel
  • Cholesterol
  • Enbucrilate

Grants and funding

This work was supported by Beijing Municipal Education Commission New Medicine Discipline Group Project [XK100270569], Foundation of Beijing of the training of outstanding talents in Excellent Young backbone individuals [2017000020124G269], Capital Medical University Research and Development Fund [PYZ2018123], National Key Research and Development Program of China [2016YFC0103909], Beijing Municipal Science & Technology Commission project [Z161100000516008], Beijing hundred-thousand-Ten thousand Talents Project: Construction of brain-targeted PBCA nanocarrier based on PEG-cholesterol co-modification and its treatment of glioma (2018A04), Beijing Hospitals Authority Ascent Plan [DFL20190803], and Capital science and technology leading talent training project [Z191100006119017].