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. 2012 Feb 1;20(3):1281-90.
doi: 10.1016/j.bmc.2011.12.020. Epub 2011 Dec 20.

A photochemical approach for controlled drug release in targeted drug delivery

Seok Ki Choi  1 , Manisha Verma, Justin Silpe, Ryan E Moody, Kenny Tang, Jeffrey J Hanson, James R Baker Jr
Affiliations

A photochemical approach for controlled drug release in targeted drug delivery

Seok Ki Choi et al. Bioorg Med Chem. .

Abstract

Photochemistry provides a unique mechanism that enables the active control of drug release in cancer-targeting drug delivery. This study investigates the light-mediated release of methotrexate, an anticancer drug, using a photocleavable linker strategy based on o-nitrobenzyl protection. We evaluated two types of the o-nitrobenzyl-linked methotrexate for the drug release study and further extended the study to a fifth-generation poly(amidoamine) dendrimer carrier covalently conjugated with methotrexate via the o-nitrobenzyl linker. We performed the drug release studies by using a combination of three standard analytical methods that include UV/vis spectrometry, (1)H NMR spectroscopy, and anal. HPLC. This article reports that methotrexate is released by the photochemical mechanism in an actively controlled manner. The rate of the drug release varies in response to multiple control parameters, including linker design, light wavelength, exposure time, and the pH of the medium where the drug release occurs.

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Figures

Figure 1
Figure 1
A proposed schematic illustrating the concept of cancer targeting drug delivery. The drug release can be controlled by the mechanism triggered by an endogenous factor (low pH, reduction, enzymes), or an external tool such as light.
Figure 2
Figure 2
A schematic for photon-based cleavage of an o-nitrobenzyl (ONB) linker as the mechanism that enables the controlled drug release
Figure 3
Figure 3
Structures of bifunctional o-nitrobenzyl (ONB) molecules 1, 2 and two methotrexate (MTX)-ONB conjugates 3, 4, derived from the linkers.
Figure 4
Figure 4
(a) UV/vis absorption spectra of methotrexate (MTX, 11 μM in PBS), and two photocleavable linkers 1 (26 μM) and 2 (33 (μM), each in an aqueous medium (0.5% MeOH/H2O); (b, c) UV/vis spectral traces of MTX-ONB conjugates 3 and 4 after exposure to UV-B (312 nm for 3), or UV-A (365 nm for 4) light as a function of irradiation time (t = 0, 1, 3, 5, 7, 10, 15 min). Each plot in the inset (b, c) shows the change in the absorption of the irradiated solution at the indicated wavelength that led to ONB-associated spectral changes.
Figure 5
Figure 5
UV light-mediated release of methotrexate (MTX) from the MTX-ONB conjugate 4 (30 (μM in 2% MeOH/H2O) by exposure to UV-A (365 nm) light. (a) HPLC traces of the irradiated solutions as a function of UV exposure time (t = 0, 1, 3, 5, 7, 10, 15 min); (b) Plots for the photochemical release of MTX from MTX-ONB conjugates 3 and 4 as a function of time exposed to UV-B (312 nm) or UV-A (365 nm) light. In the release kinetics for 3 (30 μM in 2% MeOH/H2O), the drug release refers to the amount of MTX-glycolic acid.
Figure 6
Figure 6
Photolysis of an ONB linker from the MTX-ONB conjugate 4 by exposure to UV-A light. (a) 1H NMR spectral traces acquired after UV irradiation of 4 in MeOH-d4 as a function of exposure time (t = 0 to 80 min); (b) pH effect on the rate of linker cleavage from 4 in the aqueous solution at pH 7.4 (50% CD3CN/PBS), 9.0 (20% CD3CN/D2O), or 5.0 (20% CD3CN/D2O). The percent amount of intact 4 was determined by the peak integration method applied to the ONB-associated protons Hd, He, and Hf. Each data point represents a mean value from this analysis.
Figure 7
Figure 7
Light-controlled release of methotrexate (MTX) from 11, a fifth generation PAMAM dendrimer conjugated with MTX through the photocleavable linker. The drug release was controlled by the irradiation of 11 (0.1 mg/mL, 1.96 μM) in the PBS buffer (pH 7.4), or acetate buffer (pH 4.6).
Figure 8
Figure 8
Photochemical MTX release from the dendrimer-MTX conjugate 11 (G5-FA4-MTX8). UV/vis spectra (left) and anal. HPLC traces (right) are shown for the release study performed at pH 7.4 (a) or 4.6 (b). Each spectral or chromatographic overlay is plotted as a function of UV exposure time (t = 0– 15 min). *This peak has an MTX-like UV/vis absorption profile, and its identity might be associated with MTX as the tautomer.
Figure 9
Figure 9
A summary for the amount of MTX released plotted as a function of exposure time at two different pH conditions. MTX was released from the dendrimer-MTX conjugate 11 by exposure to 365 nm light, and its amount was quantified by the AUC analysis for each of the HPLC traces shown in Figure 8.
Scheme 1
Scheme 1
Synthesis of a methotrexate (MTX)-ONB linker 3. Reagents and conditions: i) Bromoacetyl chloride, i-Pr2NEt, CH2Cl2, 0°C; ii) 2-Nitro-5-hydroxybenzyl alcohol, K2CO3, MeCN, reflux; iii) Bromoacetyl chloride, i-Pr2NEt, CH2Cl2, 0°C to rt; iv) Methotrexate, Cs2CO3, DMF, rt, 24 h (23% isolation yield); v) TFA, CH2Cl2, rt.
Scheme 2
Scheme 2
Synthesis of a methotrexate (MTX)-ONB linker 4. Reagents and conditions: i) Ethyl bromoacetate, K2CO3, DMF, rt; ii) NaOH, THF, MeOH, H2O, rt; iii) cone. HNO3, AcOH, 0°C to rt; iv) N-Boc-l,2-diaminoethane, DCC, DMAP, DMF, 0°C to rt; v) NaBH4, THF, MeOH, rt; vi) Methanesulfonyl chloride, Et3N, CHCl3, 0°C to rt; vii) Cs2CO3, Nal, methotrexate, DMF, rt; viii) TFA, CHCl3, rt, 15 min.
Scheme 3
Scheme 3
Synthesis of a folate receptor-targeting PAMAM dendrimer conjugated with methotrexate (MTX) 11. The dendrimer contains folic acid (FA) as the targeting ligand, and also carries MTX tethered at the photolabile ONB linker. Reagents and conditions: i) glutaric anhydride, Et3N, MeOH, rt, 24 h; ii) NHS, EDC, DMAP, DMF, rt, 36 h; iii) 4 (MTX-ONB linker, 15 mol. eq. per dendrimer), FA-CONHCH2CH2NH2, 5 mol. eq. per dendrimer), Et3N, DMF, rt, 36 h; iv) ethanolamine; then dialysis (MWCO 10 kDa) against phosphate-buffered saline (PBS) and deionized water.
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