Characterization of branched poly(acrylic acid) via capillary electrophoresis and NMR spectroscopy for anticancer drug targeting and delivery

Abstract

The non-selective nature of anticancer drugs leads to harmful side-effects. This work investigates the branched polymer, poly(acrylic acid), PAA, and its salt, poly(sodium acrylate), PNaA, for their potential as an anticancer drug carrier for better targeted delivery. The binding between the anticancer drug cisplatin and PNaA was investigated using capillary electrophoresis in the critical conditions (CE-CC). The average degree of branching (DB) was also quantified using NMR spectroscopy. The influence of the synthetic parameters on the DB was also investigated. The precision and accuracy of the DB quantification via NMR spectroscopy were estimated. An empirical formula was derived to assess the errors originating in the low signal to noise ratio and the user-dependent data treatment. Solubility, viscosity and moisture content were shown to influence the accuracy of DB quantification. Dissolution for most branched PAAs/PNaAs were incomplete obtaining only a maximum of 54 % for the extent of the dissolution. A set of guidelines on what should be considered for DB quantification was developed not exclusively for PAAs/PNaAs but also for other branched polymers. The DB in PAAs/PNaAs synthesized by conventional radical polymerization (CVRP) and reversible-deactivation radical polymerization (RDRP) were quantified by 13C NMR spectroscopy. The type of polymerization (CVRP or RDRP) does not play a role for the DB in PAAs/PNaAs unlike what was observed in poly(alkyl acrylates). The presence of ethanol or of chain transfer agents resulted in a decreased DB due to patching of the mid-chain radical. The influence of synthetic parameters is important for the design of branched PAAs/PNaAs. Lastly, the binding of the anticancer drug, cisplatin to PNaAs with different branching topologies (linear and hyperbranched) was monitored for the first time using CE-CC. An increase in the electrophoretic mobility (I¼) of PNaA was observed over time which suggests the formation of PNaA-cisplatin copolymers. Furthermore, the dispersity of the I¼ distributions in PNaA was determined to assess the heterogeneity of the composition of the copolymers formed through the binding reaction. Through the dispersity of the I¼ distributions, the heterogeneity of branching can be represented through which hyperbranched PNaA was observed to be more heterogeneous in branching than linear PNaA. The knowledge obtained from this work enables synthetic chemists to choose polymerization conditions to produce branching architectures of PAA/PNaA that are tailored for desired applications such as drug delivery. The characterization can be further improved by coupling CE-CC to other techniques such as size exclusion chromatography (SEC). With the enhanced knowledge on the branching in PAA/PNaAs, better drug carriers can be designed. The information on the binding process via CE-CC enables optimization of drug loading for effective targeting and delivery in the future. Additionally, the enhanced knowledge on the binding reaction and how the drug binds will be beneficial for clinical applications as CE-CC may be used as a novel approach to monitor the drug activity inside the body. As a result, the information obtained from this work can allow comprehensive knowledge on the dosage relationships specified to an individual patient's needs therefore, bringing PAA/PNaA closer to being an effective anticancer drug carrier.

Date of Award	2018
Original language	English