Identification of novel cyanoacrylate monomers for use in nanoparticle drug delivery systems prepared by miniemulsion polymerisation - A multistep screening approach

Abstract

Poly (alkyl cyanoacrylate) (PACA) polymeric nanoparticles (NPs) are promising drug carriers in drug delivery. However, the selection of commercially available alkyl cyanoacrylate (ACA) monomers is limited, because most monomers were designed for use in medical and industrial glues and later repurposed for drug encapsulation. This study therefore aimed to seek out novel ACA materials for use in NP systems using a toxicity led screening approach. A multistep strategy, including cytotoxicity screening of alcohols as degradation products of PACA (44 alcohols), NPs (14 polymers), and a final in vivo study (2 polymers) gave poly (2-ethylhexyl cyanoacrylate) PEHCA as a promising novel PACA candidate. For the first time, this work presents cytotoxicity data on several novel ACAs, PEHCA in vivo toxicity data, and miniemulsion polymerisation-based encapsulation of the cabazitaxel and NR688 in novel PACA candidates. Furthermore, several of the ACA candidates were compatible with a wider selection of lipophilic active pharmaceutical ingredients (APIs) versus commercially available controls. Combined, this work demonstrates the potential benefits of expanding the array of available ACA materials in drug delivery. Novel ACAs have the potential to encapsulate a wider range of APIs in miniemulsion polymerisation processes and may also broaden PACA applicability in other fields.

Keywords: Cabazitaxel; Drug delivery; Nanoparticle characterisation; Poly(alkyl cyanoacrylate) nanoparticles; Toxicity screening.

Graphical abstract

Fig. 1

Cellular viability (% relative to untreated control cells) after 3% (v/v) alcohol exposure in Hep G2 (blue) and LLC-PK1 (orange) cell lines. Alcohols are arranged by their number of carbon atoms (left column). Vertical lines indicate mean viability levels for the reference alcohol 2-ethyl-1-butanol, and alcohols chosen for further characterisation are marked with red asterisks. ¹indicates alcohols corresponding to commercially available ACAs. Digitonin was included as positive control. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Physicochemical properties of PACA NPs. The upper and middle panels show size, PDI, zeta potential and CBZ drug fraction for all NP batches. The lower panel shows scatter plots of size, PDI and zeta potential. ¹ indicates commercially available ACAs.

Fig. 3

Results from LDH cytotoxicity (upper panel) and MTT viability (lower panel) assays in Hep G2 and LLC-PK1 cell lines. Digitonin was included as positive control. ¹ indicates commercially available ACAs.

Fig. 4

Comparison of viability (%) after alcohol addition (orange, left axes) and IC₅₀ values after NP addition (blue, right axes) in Hep G2 and LLC-PK1 cell lines in both LDH and MTT assays. Note that the 2-PECA:BCA blend was tested for NP toxicity only, and the toxicity of the corresponding alcohol blend is therefore not included. For 2-PECA, only the toxicity of the corresponding 2-phenylethanol alcohol was tested. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Results from the rat toxicity study. A) Rat body weight change after NP injection. Number of animals at the timepoints are reduced as animals are euthanised: Day 1 and 3 (12 PEBCA, 12 PEHCA, 6 control); day 7 and 10 (8 PEBCA, 8 PEHCA, 4 control); day 14 and 16 (4 PEBCA, 4 PECHA, 2 control). B-C) Photomicrographs of tissue sections (HE staining) showing representative effects observed after i.p. NP injection. Increased amounts of fibrous connective tissue could be seen both in liver (B) and peritoneal (C) tissue.