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Application of an LC-MS/MS method for the analysis of poly (lactic-co-glycolic acid) nanoparticles for taxane chemotherapy

Date

2021-08-17

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

0000-0002-1170-9213

Type

Thesis

Degree Level

Masters

Abstract

Docetaxel and other compounds in the taxane drug family are among the most effective chemotherapeutic agents used for the treatment of solid tumors, such as breast cancer. Specific targeting of docetaxel to the tumor site would increase the safety and efficacy of the treatment. The focus of the project was to prepare optimized Poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with docetaxel, establish tandem mass spectrometric (MS/MS) fingerprints for taxane drugs, and develop a liquid chromatography (LC)-MS/MS method to quantify the encapsulated drug. Several nanoparticle formulations were prepared to optimize the nanoparticles based on their size and yield percentage using a modified solvent evaporation technique. The MS/MS fragmentation behavior of taxane compounds, namely paclitaxel, docetaxel, cabazitaxel, cephalomannine, and Baccatin III were studied in detail and a generalized MS/MS fingerprint was established for the first time. A hybrid quadrupole orthogonal time-of-flight (Q-TOF) mass spectrometer was used to obtain accurate mass measurements while MS/MS and second-generation MS/MS (MS3) analyses were performed using a triple quadrupole-linear ion trap (QqQ-LIT) device. The established MS/MS fingerprints were used to develop a multiple reaction monitoring (MRM) LC-MS/MS method to quantify docetaxel in PLGA nanoparticles. The optimized nanoparticles had a zeta potential of -23.2 ± 1.4 mV and mean particle sizes of 202.2±4.7 nm and 251.7±8.2 nm before and after freeze-drying (FD), respectively. Polydispersity index values of the nanoparticles confirmed their uniform size distribution. The taxane compounds showed common MS/MS fragmentation behavior, which allowed for the production of a universal fragmentation pattern. In addition, diagnostic product ions originated from a cleavage in the ester bond between the core diterpene ring-structure and the sidechain. The developed LC-MS/MS method could quantify docetaxel in the PLGA matrix with accuracy and precision at a quantification limit of 15.6 ng/ml. Method validation was conducted using the regulatory guidelines of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and showed acceptable values for all the tested criteria. The established general fragmentation pattern of taxanes can be used to predict the dissociation behavior of new compounds with similar structural characteristics. The developed LC-MS/MS method will be beneficial for the future analysis of docetaxel loaded polymeric nano-delivery systems.

Description

Keywords

Taxane, Nanoparticle, liquid chromatography, tandem mass spectrometry

Citation

Degree

Master of Science (M.Sc.)

Department

Pharmacy and Nutrition

Program

Pharmacy

Advisor

Citation

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DOI

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