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. 2020 Mar 13;11(1):16.
doi: 10.3390/jfb11010016.

Temperature-Responsive Molecular Assemblies Using Oligo(Ethylene Glycol)-Attached Polyamidoamine Dendron Lipids and their Functions as Drug Carriers

Takuya Hashimoto  1 , Yuji Hirai  1 , Eiji Yuba  1 , Atsushi Harada  1 , Kenji Kono  1
Affiliations

Temperature-Responsive Molecular Assemblies Using Oligo(Ethylene Glycol)-Attached Polyamidoamine Dendron Lipids and their Functions as Drug Carriers

Takuya Hashimoto et al. J Funct Biomater. .

Abstract

Temperature-responsive nanocarrier systems using external stimuli are one of the most widely investigated stimuli-responsive strategies because heat is easy and safe to use for hyperthermia and controlled drug delivery. Polyamidoamine dendron lipids (PAMAM-DLs) composed of PAMAM dendron as head group and two alkyl chains can exhibit temperature-responsive morphological change through the attachment of suitable moieties to terminal of PAMAM dendron. In this study, oligo(ethylene glycol)s including ethoxy- or methoxy-diethylene glycols were attached to the terminals of PAMAM-DL, and temperature-responsive properties of their self-assemblies were evaluated by calorimetric and turbidity measurements. In the evaluation of temperature-responsive properties, ethoxy diethylene glycol (EDEG)-attached PAMAM-DL composed of two saturated alkyl chains and PAMAM dendron with 1st generation had lipid bilayer structure and suitable cloud point for the application as drug carrier. In vitro performances of the assemblies combining EDEG-attached PAMAM-DLs with cholesteryl-oxy-poly(ethylene glycol) (PEG-Chol) was evaluated using doxorubicin (DOX) as an anticancer drug. Cellular uptake of DOX-loaded EDEG-attached PAMAM-DL/PEG-Chol assemblies was promoted at 42 °C rather than 37 °C, resulting in an effective decrease in cell viability.

Keywords: doxorubicin; morphological change; polyamidoamine dendron lipid; temperature-responsive nanocarrier.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic image of OEG-attached PAMAM dendron-lipid assembly as temperature-responsive nanocarrier.
Figure 2
Figure 2
Change in transmittance of OEG-attached PAMAM-DLs dispersions with an increase in temperature. (a) MDEG-attached PAMAM-DLs, (b) EDEG-attached PAMAM-DLs. OEG-attached PAMAM-DLs were suspended in 10 mM phosphate and 140 mM NaCl at pH 7.4.
Figure 3
Figure 3
Microcalorimetric endotherms of OEG-attached PAMAM-DLs suspended in 10 mM phosphate and 140 mM NaCl at pH 7.4. (a) MDEG-attached PAMAM-DLs, (b) EDEG-attached PAMAM-DLs.
Figure 4
Figure 4
Temperature-dependence of average diameter of EDEG-DL-G1-S/PEG-Chol assemblies with varying compositions (a), and AFM images of EDEG-DL-G1-S/PEG-Chol (95/5) assemblies at 10 and 50 °C (b). In (a), data are the average of three experiments ± SD.
Figure 5
Figure 5
Cellular uptake of EDEG-DL-G1-S/PEG-Chol (95/5) assemblies evaluated by flow cytometry (a) and CLSM observation (b). In this experiments, EDEG-DL-G1-S/PEG-Chol assemblies were fluorescently labeled using rhodamine−PE. CLSM observation was performed with incubation time of 15 min. In (a), data are the average of three experiments ± SD.
Figure 6
Figure 6
Cellular uptake and intracellular distribution of DOX-loaded EDEG-DL-G1-S/PEG-Chol (95/5) assemblies. (a) Cellular uptake evaluated by flow cytometry detected DOX fluorescence; (b) CLSM images of HeLa cells treated with DOX-loaded EDEG-DL-G1-S/PEG-Chol assemblies fluorescently labeled using NBD−PE. HeLa cells were incubated with DOX-loaded EDEG-DL-G1-S/PEG-Chol assemblies for 15 min.
Figure 7
Figure 7
Cell viability of HeLa cells treated with DOX-loaded EDEG-DL-G1-S/PEG-Chol assemblies (a) and DEG-DL-G1-S/PEG-Chol assemblies without DOX loading (b) at 37 °C and 42 °C. Cell viabilities were evaluated by MTT assay. Data are the average of three experiments ± SD. In (a), DOX was loaded into the assemblies at DOX/lipid (mol/mol) = 0.41 ± 0.04. In (b), lipid concentration was 0.5 mM, and this concentration corresponds to 5-time higher than 20 mg/L of DOX in DOX-loaded EDGE-DL-G1-S/PEG-Chol assemblies.
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