Optimizing the encapsulation of SN-38 in PCL-b-PEG polymer nanoparticles for cancer therapy
Date
2024-01-05
Authors
Silverman, Lisa
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Abstract
Background: In this study, we address challenges encapsulating the anticancer agent, SN-38, in polymer nanoparticles (PNPs) for improved cancer treatment. SN-38 is particularly difficult to encapsulate due to its poor solubility in water and many solvents.
Methods: PNPs were synthesized using both bulk and microfluidic nanoprecipitation, and characterized for physico-chemical properties, release kinetics, and cytotoxicity and tumor penetration in 2D cell culture and tumor spheroids. Different formulations of PNPs, including different ratios of SN-38 and curcumin (CUR), and block co-polymers with different PEG terminal endgroups were compared to find the optimal formulation for encapsulating SN-38.
Results: By co-encapsulating CUR with SN-38, we can achieve increased SN-38 encapsulation efficiencies in co-loaded SN-38/CUR-PNPs by up to ten-fold as compared to PNPs encapsulating SN-38 alone. Moreover, a two-phase microfluidic reactor demonstrates similar trends regarding SN-38 content with CUR co-encapsulation, compared to bulk nanoprecipitation methods. Our findings also reveal a decrease in PNP polydispersity from 0.34 to 0.07 as the initial CUR-to-polymer initial ratio increases from 0 to 10.
Our first cytotoxicity studies show adding CUR does not significantly affect SN-38 potency. However, we observed significant differences in the potencies of SN-38/CUR-PNP formulations depending on formulation. An optimized formulation exhibited sub-nanomolar cytotoxicity against A204 cells, surpassing the potency of free SN-38 or PNPs containing only SN-38.
We find that incorporating a thiol terminal end group onto the PEG in the PNP resulted in a doubling of SN-38 encapsulation efficiency from 10% in the reference SN-38/CUR-PNP-OCH3 to 21% in SN-38/CUR-PNP-SH, but that this increase is only seen when the SN-38/CUR drug mixture is used, and not when the drugs are encapsulated individually.
Confocal microscopy shows encouraging results regarding PNP penetration throughout tumor spheroids, but EC50 cytotoxicity results in both 2D and 3D culture models show limited efficacy in cell killing of our formulations in 3D models, and although the SH-PNP formulation shows the best results in 2D models, the reference OCH3 formulation shows better performance in the 3D models.
Conclusions: Our study presents a co-encapsulation strategy that significantly enhances SN-38 encapsulation efficiency within PNPs for improved cancer treatment strategies. These findings contribute to overcoming challenges associated with poor solubility of SN-38 and paves the way for the use of SN-38 in the clinic.
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Keywords
nanoparticles, nanomedicine, block copolymer, SN-38, microfluidics, cancer