A novel temperature-responsive micelle for enhancing combination therapy

Abstract

A novel thermosensitive polymer p(N-isopropylacrylamide-co-poly[ethylene glycol] methyl ether acrylate)-block-poly(epsilon-caprolactone), p(NIPAAM-co-PEGMEA)-b-PCL, was synthesized and developed as nanomicelles. The hydrophobic heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin and the photosensitizer cyanine dye infrared-780 were loaded into the core of the micelles to achieve both chemotherapy and photothermal therapy simultaneously at the tumor site. The release of the drug could be controlled by varying the temperature due to the thermosensitive nature of the micelles. The micelles were less than 200 nm in size, and the drug encapsulation efficiency was >50%. The critical micelle concentrations were small enough to allow micelle stability upon dilution. Data from cell viability and animal experiments indicate that this combination treatment using photothermal therapy with chemotherapy had synergistic effects while decreasing side effects.

Keywords:

• thermosensitive
• photothermal therapy
• chemotherapy
• nanocarrier
• control release
• synergistic effect

Supplementary materials

Figure S1 Preparation of IR-780/17-AAG–coloaded micelles.

Abbreviations: NIPAAM, N-isopropylacrylamide; PEGMEA, poly(ethylene glycol) methyl ether acrylate; PCL, poly(epsilon-caprolactone); 17-AAG, 17-allylamino-17-demethoxygeldanamycin; IR, infrared.

Figure S2 ¹H NMR spectra of CPPA-PCL (macro-CPPA) and p(NIPAAM-co-PEGMEA)-b-PCL in CDCl₃.

Note: The a–f correspond with the left chemical structure and they can also be noted on the chemical structure (δHa, 4.05 ppm; δHb, 1.4 ppm; δHc, 2.3 ppm; and δHd, 1.65 ppm), NIPAAM (δHe, 1.1 ppm), and PEGMEA (δHf, 3.6 ppm).

Abbreviations: NMR, nuclear magnetic resonance; CPPA, 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid; PCL, poly(epsilon-caprolactone); NIPAAM, N-isopropylacrylamide; PEGMEA, poly(ethylene glycol) methyl ether acrylate; CDCl₃, deuterated chloroform.

Figure S3 GPC spectrum of macro-CPPA and p(NIPAAM-co-PEGMEA)-b-PCL copolymers.

Abbreviations: GPC, gel permeationchromatography;CPPA, 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid; PCL,poly(epsilon-caprolactone); NIPAAM, N-isopropylacrylamide; PEGMEA, poly(ethylene glycol) methyl ether acrylate; MW, molecular weight.

Figure S4 Plot to determine the critical micelle concentration.

Abbreviations: I3, emission intensity at 383 nm; I1, emission intensity at 371 nm.

Figure S5 Dynamic light scattering to determine micelle size (A) and zeta potential (B).

Abbreviations: PCL, poly(epsilon-caprolactone); NIPAAM, N-isopropylacrylamide; PEGMEA, poly(ethylene glycol) methyl ether acrylate; 17-AAG, 17-allylamino-17-demethoxygeldanamycin; IR, infrared.

Figure S6 Absorbance curve of empty micelle solution as a function of temperature.

Abbreviation: OD, optical density.

Figure S7 The viability of HCT-116 cells treated with micelles.

Notes: (A) The cytotoxicity of empty micelles on HCT-116 cells after 24 hours. (B) The cytotoxicity of free 17-AAG– and 17-AAG–loaded micelles on HCT-116 cells after 24 hours.

Abbreviations: 17-AAG, 17-allylamino-17-demethoxygeldanamycin; HCT, human colorectal adenocarcinoma.

Acknowledgments

This research was supported by grants from the National Science Council of the Republic of China (NSC 102-2320-B-002-038-MY3, NSC 102-2221-E-002-037-MY3).

Author contributions

Cheng-Liang Peng: experimental design, performance of experiments, providing suggestions, and manuscript revision; Yuan-I Chen: experimental design and manuscript writing; Hung-Jen Liu: experimental design and performance of experiments; Pei-Chi Lee: participation in the experiment involving animal model; Tsai-Yueh Luo: experimental suggestions; Ming-Jium Shieh: experimental suggestions and manuscript revision. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.