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. 2023 Jul 26;8(31):28165-28184.
doi: 10.1021/acsomega.3c01375. eCollection 2023 Aug 8.

Surface-Modified Biobased Polymeric Nanoparticles for Dual Delivery of Doxorubicin and Gefitinib in Glioma Cell Lines

Ms Farheen  1 , Md Habban Akhter  1 , Havagiray Chitme  1 , Muath Suliman  2 , Mariusz Jaremko  3 , Abdul-Hamid Emwas  4
Affiliations

Surface-Modified Biobased Polymeric Nanoparticles for Dual Delivery of Doxorubicin and Gefitinib in Glioma Cell Lines

Ms Farheen et al. ACS Omega. .

Abstract

Glioma is a malignant form of brain cancer that is challenging to treat due to the progressive growth of glial cells. To target overexpressed folate receptors in glioma brain tumors, we designed and investigated doxorubicin-gefitinib nanoparticles (Dox-Gefit NPs) and folate conjugated Dox-Gefit NPs (Dox-Gefit NPs-F). Dox-Gefit NPs and Dox-Gefit NPs-F were characterized by multiple techniques including Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1H NMR), and transmission electron microscopy (TEM). In vitro release profiles were measured at both physiological and tumor endosomal pH. The cytotoxicity of the Dox-Gefit NP formulations was measured against C6 and U87 glioma cell lines. A hemolysis assay was performed to investigate biocompatibility of the formulations, and distribution of the drugs in different organs was also estimated. The Dox-Gefit NPs and Dox-Gefit NPs-F were 109.45 ± 7.26 and 120.35 ± 3.65 nm in size and had surface charges of -18.0 ± 3.27 and -20.0 ± 8.23 mV, respectively. Dox-Gefit NPs and Dox-Gefit NPs-F significantly reduced the growth of U87 cells, with IC50 values of 9.9 and 3.2 μM. Similarly, growth of the C6 cell line was significantly reduced, with IC50 values of 8.43 and 3.31 μM after a 24 h incubation, in Dox-Gefit NPs and Dox-Gefit NPs-F, respectively. The percentage drug releases of Dox and Gefit from Dox-Gefit NPs at pH 7.4 were 60.87 ± 0.59 and 68.23 ± 0.1%, respectively. Similarly, at pH 5.4, Dox and Gefit releases from NPs were 70.87 ± 0.28 and 69.24 ± 0.12%, respectively. Biodistribution analysis revealed that more Dox and Gefit were present in the brain than in the other organs. The functionalized NPs inhibited the growth of glioma cells due to high drug concentrations in the brain. Folate conjugated NPs of Dox-Gefit could be a treatment option in glioma therapy.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of Dox (A) and Gefit (B).
Figure 2
Figure 2
Schematic representation of Dox-Gefit NPs-F preparation.
Figure 3
Figure 3
NP diagnostic plots. (A) Normal % probability plot of particle size. (B) Externally studentized residuals vs. predicted plot of particle size. (C) Externally studentized residuals vs runs of particle size. (D) Normal % probability plot of PDI. (E) Externally studentized residuals vs predicted plot of PDI. (F) Externally studentized residuals vs run of PDI. (G) Normal % probability plot of % drug release. (H) Externally studentized residuals vs. predicted plot of % drug release. (I) Externally studentized residuals vs run of % drug release.
Figure 4
Figure 4
3-D response surface plots. (A–I) Comparative effective surfactant conc., polymer conc., and sonication time on particle size (A–C), PDI (D–F), and % drug release (G–I).
Figure 5
Figure 5
Dox-Gefit NP and Dox-Gefit NPs-F particle size and ζ potential. (A) Dox-Gefit NP size distribution. (B) Dox-Gefit NPs-F size distribution. (C) ζ Potential of Dox-Gefit NPs. (D) ζ Potential of Dox-Gefit NPs-F.
Figure 6
Figure 6
Transmission electron microscopy of Dox-Erlo NPs (A) and Dox-Erlo NPs-F (B).
Figure 7
Figure 7
DSC thermogram Gefit (A), Dox (B), cinnamon biopolymer (C), PVA (D), Dox-Gefit NPs (E), and Dox-Gefit NPs-F (F).
Figure 8
Figure 8
FT-IR spectra of Gefit (A), Dox (B), cinnamon polymer (C), PVA (D), Dox-Gefit NPs (E), and Dox-Gefit NPs–F (F).
Figure 9
Figure 9
(A) Schematic diagram of amide-bond formation in Dox-Gefit NPs-F. (B) 1H NMR spectrum of Dox-Gefit NPs-F.
Figure 10
Figure 10
XRD diffraction analyses of (A) Gefit, (B) Dox, (C) cinnamon biopolymer, (D) Dox-Gefit NPs, and (E) Dox-Gefit NPs-F.
Figure 11
Figure 11
In vitro drug release of Gefit and Dox. (A) pH 5.4 and (B) pH 7.4.
Figure 12
Figure 12
Hemolysis of NPs. (A) Percentage hemolysis with placebo NPs, Dox-Gefit NPs, Dox-Gefit NPs-F, Triton-X-100, and normal saline. (B) Tubes containing blood after exposure to NPs, normal saline, or Triton-X-100.
Figure 13
Figure 13
Cell viability study. (A) Bar graph showing the percentage U87 cell viability after 24 h treatment with different concentrations of pure Dox, pure Gefit, Dox-Gefit NPs, Dox-Gefit NPs-F, placebo NPs, or placebo NPs-F, and (B) showing cell viability in the C6 glioma cell line after 24 h of the same treatment. The bar graphs show the mean ± S.D. (n = 3). Level of significance *(p < 0.05), **(p < 0.01), ***(p < 0.001), ****(p < 0.0001) compared to pure Dox and pure Gefit.
Figure 14
Figure 14
Biodistribution of Dox and Gefit in the heart, liver, kidney, brain, blood, and lungs. (A) Dox concentration from plain Dox, Dox-Gefit NPs, and Dox-Gefit NPs-F; (B) Gefit concentration from plain Gefit, Dox-Gefit NPs, and Dox-Gefit NPs-F.
Figure 15
Figure 15
Nanodrug stability in 10% FBS. UV spectrum of Dox-Gefit NPs-F incubated in 10% FBS at corresponding times of 0.5, 1, 4, and 6 h (A); alternation in particle size (B) and ζ potential of Dox-Gefit NPs-F (C) at the end of 24 h.
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