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. 2020 Aug 3;17(8):2840-2848.
doi: 10.1021/acs.molpharmaceut.0c00242. Epub 2020 Jul 10.

Drug Loading in Poly(butyl cyanoacrylate)-Based Polymeric Microbubbles

Mengjiao Liu  1 , Anshuman Dasgupta  1 , Patrick Koczera  1   2 , Sandra Schipper  1 , Dirk Rommel  3 , Yang Shi  1 , Fabian Kiessling  1 , Twan Lammers  1
Affiliations

Drug Loading in Poly(butyl cyanoacrylate)-Based Polymeric Microbubbles

Mengjiao Liu et al. Mol Pharm. .

Abstract

Microbubbles (MB) are routinely used ultrasound (US) contrast agents that have recently attracted increasing attention as stimuli-responsive drug delivery systems. To better understand MB-based drug delivery, we studied the role of drug hydrophobicity and molecular weight on MB loading, shelf-life stability, US properties, and drug release. Eight model drugs, varying in hydrophobicity and molecular weight, were loaded into the shell of poly(butyl cyanoacrylate) (PBCA) MB. In the case of drugs with progesterone as a common structural backbone (i.e., for corticosteroids), loading capacity and drug release correlated well with hydrophobicity and molecular weight. Conversely, when employing drugs with no structural similarity (i.e., four different fluorescent dyes), loading capacity and release did not correlate with hydrophobicity and molecular weight. All model drug-loaded MB formulations could be equally efficiently destroyed upon exposure to US. Together, these findings provide valuable insights on how the physicochemical properties of (model) drug molecules affect their loading and retention in and US-induced release from polymeric MB, thereby facilitating the development of drug-loaded MB formulations for US-triggered drug delivery.

Keywords: PBCA; corticosteroids; drug delivery; microbubbles; theranostics; ultrasound.

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Conflict of interest statement

Competing interests

FK and TL hold a patent on multimodal US imaging using PBCA-based polymeric microbubbles.

Figures

Graphic abstract
Graphic abstract
Figure 1
Figure 1. Schematic study setup.
Poly(butyl cyanoacrylate)-based (PBCA) polymeric microbubbles (MB) were synthesized by anionic polymerization of BCA. Upon loading of eight different (model) drugs into the shell of PBCA MB, several characterization techniques were employed to study drug loading capacity, drug retention, ultrasound (US) properties and US-induced drug release.
Figure 2
Figure 2. Overview of the (model) drugs used in this study.
Corticosteroids with progesterone as a common structural derivative (whose hydrophobicity and molecular weight increased simultaneously; left panel) and fluorescent dyes with no common structural derivative (whose hydrophobicity and molecular weight did not increase simultaneously; right panel) were loaded into the shell of PBCA MB.
Figure 3
Figure 3. Loading capacity and encapsulation efficiency of PBCA MB.
A-B: Representative fluorescence microscopy image exemplifying successful loading of coumarin 6 into the shell of PBCA MB. C-D: Quantification of corticosteroids in MB showing that an increase in hydrophobicity and molecular weight results in an increased encapsulation efficiency and loading capacity. E-F: Quantitative analysis of fluorophore-loaded MB showing that with increasing hydrophobicity, loading capacity and encapsulation efficiency also do tend to increase, with the exception of rhodamine B. Note that the color-coding of the plotted lines corresponds to the degree of hydrophobicity. Values represent mean ± standard deviation of three different batches of drug-loaded MB, measured in triplicates.
Figure 4
Figure 4. Shelf-life stability of drug-loaded PBCA MB.
A-B: Quantitative analysis of drug retention, showing that at both the 1:20 and 1:2 feed ratios, corticosteroid content did not decrease significantly over time and exemplifying that all four drugs were efficiently retained in the MB shell even after 12 weeks of storage. C-D: Quantitative analysis of fluorophore retention showing that fluorescent dyes were less efficiently retained at the higher feed ratio of 1:2 as compared to lower feed ratio of 1:20. Additionally, less hydrophobic model drugs were less efficiently retained in the MB shell and vice-versa. Note that the color-coding of the plotted lines corresponds to the degree of hydrophobicity. Values represent mean ± standard deviation of three different batches of drug-loaded MB, measured in triplicates. All statistical comparisons were made with respect to week 0. ** and *** indicate p < 0.01 and p < 0.001, respectively.
Figure 5
Figure 5. Ultrasound analysis of drug-loaded PBCA MB.
A-B: A representative B-mode and contrast-mode image of all drug-loaded PBCA MB showing that ultrasound (US) contrast is efficiently generated at low powers, while at high powers, MB are destroyed (as evidenced by the lack of US contrast). C-D: Quantitative analysis of MB destruction showing that there are no significant differences between the different drug-loaded PBCA MB, and demonstrating that US properties are independent of the hydrophobicity and molecular weight of the encapsulated drug. Note that the color-coding of the plotted lines corresponds to the degree of hydrophobicity. Values represent mean ± standard deviation of three different batches of drug-loaded MB, measured in triplicates.
Figure 6
Figure 6. US-induced drug release from PBCA MB.
A: Quantitative analysis of corticosteroid release showing that hydrophobicity and molecular weight negatively affect US-induced drug release. B: Fluorophore release from the MB shell did not show a relationship to hydrophobicity and molecular weight. Note that color-coding corresponds to the degree of hydrophobicity. Values represent mean ± standard deviation of three different batches of drug-loaded MB, measured in triplicates. All statistical comparisons were made respect to dexamethasone and rhodamine B in panel A and B respectively. *, ** and *** indicate p < 0.05, p < 0.01 and p < 0.001 respectively.
Figure 7
Figure 7. Correlating the hydrophobicity (top) and molecular weight (bottom) of corticosteroid drugs with the characteristics of shell-loaded PBCA MB.
Loading capacity and drug release of corticosteroid-loaded MB showed a good correlation with both hydrophobicity and molecular weight. Symbols: ● = Dexamethasone. ■ = Budesonide. ★ = Halcinonide. ◆ = Ciclesonide.
Figure 8
Figure 8. Correlating hydrophobicity (top) and molecular weight (bottom) of fluorophores with the characteristics of shell-loaded PBCA MB.
Only shelf-life stability showed a good correlation with both hydrophobicity and molecular weight. Symbols: ● = Rhodamine B. ■ = Nile red. ★ = Coumarin 6. ◆ = Pyrene.
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