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. 2023 Jul 23;15(14):3133.
doi: 10.3390/polym15143133.

Design, Synthesis, and Comparison of PLA-PEG-PLA and PEG-PLA-PEG Copolymers for Curcumin Delivery to Cancer Cells

Neda Rostami  1 , Farzaneh Faridghiasi  2 , Aida Ghebleh  3 , Hadi Noei  4 , Meisam Samadzadeh  5 , Mohammad Mahmoudi Gomari  6 , Alireza Tajiki  1 , Majid Abdouss  1 , Alireza Aminoroaya  7 , Manisha Kumari  7 , Reza Heidari  8 , Vladimir N Uversky  9 , Bryan R Smith  7
Affiliations

Design, Synthesis, and Comparison of PLA-PEG-PLA and PEG-PLA-PEG Copolymers for Curcumin Delivery to Cancer Cells

Neda Rostami et al. Polymers (Basel). .

Abstract

Curcumin (CUR) has potent anticancer activities, and its bioformulations, including biodegradable polymers, are increasingly able to improve CUR's solubility, stability, and delivery to cancer cells. In this study, copolymers comprising poly (L-lactide)-poly (ethylene glycol)-poly (L-lactide) (PLA-PEG-PLA) and poly (ethylene glycol)-poly (L-lactide)-poly (ethylene glycol) (PEG-PLA-PEG) were designed and synthesized to assess and compare their CUR-delivery capacity and inhibitory potency on MCF-7 breast cancer cells. Molecular dynamics simulations and free energy analysis indicated that PLA-PEG-PLA has a higher propensity to interact with the cell membrane and more negative free energy, suggesting it is the better carrier for cell membrane penetration. To characterize the copolymer synthesis, Fourier transform-infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR) were employed, copolymer size was measured using dynamic light scattering (DLS), and their surface charge was determined by zeta potential analysis. Characterization indicated that the ring-opening polymerization (ROP) reaction was optimal for synthesizing high-quality polymers. Microspheres comprising the copolymers were then synthesized successfully. Of the two formulations, PLA-PEG-PLA experimentally exhibited better results, with an initial burst release of 17.5%, followed by a slow, constant release of the encapsulated drug up to 80%. PLA-PEG-PLA-CUR showed a significant increase in cell death in MCF-7 cancer cells (IC50 = 23.01 ± 0.85 µM) based on the MTT assay. These data were consistent with gene expression studies of Bax, Bcl2, and hTERT, which showed that PLA-PEG-PLA-CUR induced apoptosis more efficiently in these cells. Through the integration of nano-informatics and in vitro approaches, our study determined that PLA-PEG-PLA-CUR is an optimal system for delivering curcumin to inhibit cancer cells.

Keywords: PEG; PLA; biomaterials; breast cancer; copolymer; curcumin; drug delivery; nano-informatics.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic representation of the work cycle utilized in this study.
Figure 2
Figure 2
RMSD values of PLA-PEG-PLA and PEG-PLA-PEG.
Figure 3
Figure 3
RMSF analysis for PLA-PEG-PLA and PEG-PLA-PEG.
Figure 4
Figure 4
Comparative RDF to analyze the water penetration capability to pass through POPC in PLA-PEG-PLA and PEG-PLA-PEG systems (the graphs of the designed systems aligned with each other).
Figure 5
Figure 5
SASA analysis for PLA-PEG-PLA and PEG-PLA-PEG.
Figure 6
Figure 6
Contact number analysis for PLA-PEG-PLA and PEG-PLA-PEG to POPC membrane.
Figure 7
Figure 7
Distance between target copolymers and POPC membrane.
Figure 8
Figure 8
MSD evaluation for PLA-PEG-PLA and PEG-PLA-PEG. (A) Transverse diffusion, (B) lateral diffusion, and (C) polar and non-polar areas of block copolymers via Gauss View.
Figure 9
Figure 9
(A) The FT-IR spectra of copolymers, (B) 1H-NMR spectra of PLA-PEG-PLA, and (C) 1H-NMR spectra of PEG-PLA-PEG.
Figure 10
Figure 10
Characterization and morphology investigation. (A) Zeta potential and polydispersity index (PDI) measurements of copolymers, (B) average particle size diameter of PEG-PLA-PEG, (C) average particle size diameter of PLA-PEG-PLA, (D) SEM images of PLA-PEG-PLA, and (E) SEM images of PEG-PLA-PEG.
Figure 11
Figure 11
Contact angle measurements. Values represent the mean ± SD, and data were analyzed using one-way ANOVA (n = 4). * p < 0.05, ** p < 0.01, and *** p < 0.001.
Figure 12
Figure 12
In vitro release of free curcumin and curcumin-loaded PLA-PEG-PLA and PEG-PLA-PEG at various w/w ratios.
Figure 13
Figure 13
Evaluating the inhibitory effect of curcumin-copolymers on MCF-7 cancer cells at 48 h. Values represent the mean ± SD, and data were evaluated using one-way ANOVA (n = 3). * p < 0.05, ** p < 0.01, and *** p < 0.001.
Figure 14
Figure 14
The figure illustrates the alterations in the expression of Bax (A), Bcl-2 (B), and hTERT (C) genes following the administration of curcumin and the designed copolymers over a 48-hour period. Gene expression analysis was conducted using one-way ANOVA with a sample size of three (n = 3). Statistical significance levels are denoted as * p < 0.05 and ** p < 0.01.
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