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. 2018 Aug 17;8(51):29321-29337.
doi: 10.1039/c8ra04580a. eCollection 2018 Aug 14.

Photo-responsive polymeric micelles and prodrugs: synthesis and characterization

Shiu-Wei Wang  1 , Yin-Ku Lin  2 , Jia-You Fang  3 , Ren-Shen Lee  1
Affiliations

Photo-responsive polymeric micelles and prodrugs: synthesis and characterization

Shiu-Wei Wang et al. RSC Adv. .

Abstract

Bio-recognizable and photocleavable amphiphilic glycopolymers and prodrugs containing photodegradable linkers (i.e. 5-hydroxy-2-nitrobenzyl alcohol) as junction points between bio-recognizable hydrophilic glucose (or maltose) and hydrophobic poly(α-azo-ε-caprolactone)-grafted alkyne or drug chains were synthesized by combining ring-opening polymerization, nucleophilic substitution, and "click" post-functionalization with alkynyl-pyrene and 2-nitrobenzyl-functionalized indomethacin (IMC). The block-grafted glycocopolymers could self-assemble into spherical photoresponsive micelles with hydrodynamic sizes of <200 nm. Fluorescence emission measurements indicated the release of Nile red, a hydrophobic dye, encapsulated by the Glyco-ONB-P(αN3CL-g-alkyne) n micelles, in response to irradiation caused by micelle disruption. Light-triggered bursts were observed for IMC-loaded or -conjugated micelles during the first 5 h. Following light irradiation, the drug release rate of IMC-conjugated micelles was faster than that of IMC-loaded micelles. Selective lectin binding experiments confirmed that glycosylated Glyco-ONB-P(αN3CL-g-alkyne) n could be used in bio-recognition applications. The nano-prodrug with and without UV irradiation was associated with negligible levels of toxicity at concentrations of less than 30 μg mL-1. The confocal microscopy and flow cytometry results indicated that the uptake of doxorubicin (DOX)-loaded micelles with UV irradiation by HeLa cells was faster than without UV irradiation. The DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles effectively inhibited HeLa cells' proliferation with a half-maximal inhibitory concentration of 8.8 μg mL-1.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Synthesis photo-triggered Glyco-ONB-P(αN3CL-g-alkyne)n and prodrug.
Fig. 1
Fig. 1. Representative 1H NMR spectroscopy: (A) HONB-P(αN3CL)10, (B) (4-propargoxy-2-nitro)benzyl indomethacinoate (PONBIMC), (C) HONB-P(αN3CL-g-PONBIMC)10, and (D) Gluco-ONB-P(αN3CL-g-PONBIMC)10.
Fig. 2
Fig. 2. IR spectra of (A) HONB-P(αN3CL)10, (B) HONB-P(αN3CL-g-PONBIMC)10, (C) Gluco-ONB-P(αN3CL-g-PONBIMC)10.
Fig. 3
Fig. 3. GPC curve of (A) HONB-P(αN3CL)10, (B) HONB-P(αN3CL-g-PONBIMC)10, and (C) Gluco-ONB-P(αN3CL-g-PONBIMC)10.
Fig. 4
Fig. 4. (A) Excitation spectra of pyrene Gluco-ONB-P(αN3CL-g-Ppyren)12 micelles monitored at λem = 390 nm with different concentrations. (B) Plot of the I343/I335 intensity ratio (from pyrene excitation spectra: pyrene concentration = 6.1 × 10−7 M) versus the logarithm of the concentration (log C) of Glyco-ONB-P(αN3CL-g-alkyne)n: (■) Gluco-ONB-P(αN3CL-g-Ppyren)12, (▲) Gluco-ONB-P(αN3CL-g-Ppyren2/-Hexy24), (▼) Malto-ONB-P(αN3CL-g-Ppyren2/-Hexy24).
Fig. 5
Fig. 5. TEM and size distribution of Gluco-ONB-P(αN3CL-g-Ppyren2/-Hexy24) micelles: (A) blank, (B) IMC-loaded, and (C) after UV irradiation 6 h.
Fig. 6
Fig. 6. (A) Time-dependent UV-vis spectra changes of the IMC-conjugate Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles treatment under UV irradiation (352 nm, 8 W × 8 W), and DLS and TEM changes of Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles: without irradiation (B and D), and with irradiation for 6 h (C and E).
Fig. 7
Fig. 7. Size distribution of Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelle in the presence of bovine serum albumin (10 wt%) for different time intervals: (A) blank, (B) 30 min, (C) 4 h, (D) 6 d, and (E) 14 d.
Fig. 8
Fig. 8. (A) Fluorescence spectra change of Nile red-loaded Gluco-ONB-P(αN3CL-g-Ppyren2/-Hexy24) micelle in PBS (0.01 M, pH 7.4) in the presence of UV irradiation (352 nm) at 25 °C, (B) normalized fluorescence emission intensity vs. time of irradiation.
Fig. 9
Fig. 9. IMC release (A) the IMC-loaded micelle of Gluco-ONB-P(αN3CL-g-Ppyren2/-Hexy24) in the presence of UV irradiation (●) and without irradiation (■), (B) the IMC-conjugate micelle of Gluco-ONB-P(αN3CL-g-PONBIMC)10 in the presence of UV irradiation (●) and without irradiation (■) in PBS (0.01 M, pH 7.4) at 37 °C.
Fig. 10
Fig. 10. The absorbance (450 nm) of the Gluco-ONB-P(αN3CL-g-PONBIMC)10 solution upon reaction with lectin Con A (2 mg mL−1) in PBS buffer: concentration 0.2 mg mL−1 with lectin Con A (▼) or without lectin Con A (▲), concentration 0.1 mg mL−1 with lectin Con A (●) or without lectin Con A (■).
Fig. 11
Fig. 11. The cell viabilities of HeLa cells treated: (A) with various concentrations of Gluco-ONB-P(αN3CL-g-PONBIMC)10 before UV exposure and after 1 h of UV irradiation, (B) with DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles (■), and free DOX (●) for 48 h. Data are shown as mean ± S.E. (n = 3).
Fig. 12
Fig. 12. (A) Flow cytometric histogram profiles of HeLa cells treated with free DOX (left), and DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 (right) for 1, 5, and 60 min. Control groups were cells that did not receive any treatment, representing basal fluorescent levels, and (B) geometric mean fluorescence intensities of free DOX (black) and DOX-loaded micelles (gray). Data shown mean ± S. E. (n = 3).
Fig. 13
Fig. 13. Fluorescent microscopic images of HeLa cells incubated with free DOX (254.7 ng mL−1) or DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles for different time intervals: (A) free DOX, and (B) DOX-loaded micelles for 1 min; (C) free DOX, and (D) DOX-loaded micelles for 60 min. For each row, images for left to right show the cells with Hoechst 33342 nuclear staining, DOX fluorescence, and the merged image (scale bar 50 μm; brightness not proportional to fluorescence intensity).
Fig. 14
Fig. 14. (A) Flow cytometric histogram profiles of HeLa cells treated with free DOX (left), and after 5 min UV irradiation DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles (right) for 1, 5, and 60 min. Control groups were cells that did not receive any treatment, representing basal fluorescent levels, and (B) geometric mean fluorescence intensities of free DOX (black) and after 5 min UV irradiation DOX-loaded micelles (gray). Data shown mean ± S. E. (n = 3).
Fig. 15
Fig. 15. Fluorescent microscopic images of HeLa cells incubated with free DOX (254.7 ng mL−1) or after 5 min UV irradiation DOX-loaded Gluco-ONB-P(αN3CL-g-PONBIMC)10 micelles for 60 min: (A) free DOX, and (B) after UV irradiation DOX-loaded micelles. For each row, images for left to right show the cells with Hoechst 33342 nuclear staining, DOX fluorescence, and the merged image (scale bar 50 μm; brightness not proportional to fluorescence intensity).
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