Versatile pH-response Micelles with High Cell-Penetrating Helical Diblock Copolymers for Photoacoustic Imaging Guided Synergistic Chemo-Photothermal Therapy - PubMed (original) (raw)
. 2016 Sep 13;6(12):2170-2182.
doi: 10.7150/thno.16633. eCollection 2016.
Affiliations
- PMID: 27924155
- PMCID: PMC5135441
- DOI: 10.7150/thno.16633
Versatile pH-response Micelles with High Cell-Penetrating Helical Diblock Copolymers for Photoacoustic Imaging Guided Synergistic Chemo-Photothermal Therapy
Shengyu Shi et al. Theranostics. 2016.
Abstract
With high optical absorption efficiency, near infrared (NIR) dyes have been proposed as theranostic agents for fluorescence imaging, photoacoustic imaging (PAI), and photothermal therapy (PTT). However, inherent hydrophobicity and short circulation time of small molecule hinder the further biomedical application. Herein smart amphiphilic copolymer was synthesized containing IR780/camptothecin@poly(ε-caprolactone) (IR780/CPT@PCL) as core, helical poly(phenyl isocyanide) (PPI) blocks as shell with the pH-responsive rhodamine B (RhB) moieties in the core-shell interface. With hydrophilic helical PPI coronas, these micelles present significantly enhanced cell-penetrating capacity that plays a key role in facilitating intracellular delivery of various cargos. By encapsulating CPT and IR780 molecules, the multifunctional self-assemble probe has huge potential to realize functional cooperativity and adaptability for cancer diagnosis and therapy. The in vitro and in vivo experimental results demonstrate that the pH-triggered fluorescent responsiveness and strong acoustic generation permit them efficient fluorescent and PA signal sensing for cancer diagnosis. Moreover, with 808 nm laser irradiation, the generated heat significantly improves the drug release from PCL core, leading to synergetic chemo-photothermal therapy and decreases tumor recurrence rates in mice. Overall, the biocompatible multifunctional micelles with these combined advantages can potentially be utilized for PAI guided disease diagnosis and tumor ablation.
Keywords: cell penetration; helical poly(phenyl isocyanide); micelles; photoacoustic imaging; theranostics..
Conflict of interest statement
The authors have declared that no competing interest exists.
Figures
Scheme 1
Schematic representation of ICM for multi-mode imaging guided synergistic chemo-photothermal treatment of tumors upon their internalization by cells via endocytosis.
Figure 1
(A) SEC traces obtained for PM, PPI(-RhB)-OH, and PCL(-RhB)-ClPd(PEt3)2 polymers, using THF as eluent. (B) 1H and (C) 31P NMR spectra obtained for the PM diblock copolymers. (D) AFM image obtained for PM copolymers dried from THF solution, inserted image showed the magnified photo for the helical fibers. (E) DLS spectra obtained for PM, PPI(-RhB)-OH, and PCL(-RhB)-ClPd(PEt3)2 polymers in THF or in water. (F) TEM image observed for PM dried from aqueous dispersion. (G) Absorption spectra recorded for PM, IM, CM, and ICM in water. (H) Fluorescent emission spectrum record for an aqueous dispersion of ICM (excitation = 790 nm). (I) TEM image observed for ICM dried from the aqueous dispersion.
Figure 2
(A) Incubation duration-dependent CLSM images of live HeLa cells when culturing at 37 ℃ with Nile red@mPEG-PCL and Nile red@PPI-PCL micelles. The red channel was excited at 550 nm. (B) Typical time dependence of the emission intensity recorded during the ring-opening reaction of RhB moieties in PM induced by a stopped-flow pH jump from 7.4 to 5.5. (C) Change in the fluorescence emission intensity of PM at 25 ℃ when micellar dispersion pH was cycled between 5.5 and 7.4.
Figure 3
(A) NIR thermal imaging of ICM and PM after treated by 808 nm laser at power density of 1 W cm-2 for 150 seconds. (B) The CPT release profile of ICM with and without laser irradiation (808 nm, 1 W cm-2) for 12 h. (C) The viability of HeLa cells treated with (+; for 10 min) or without (-) laser irradiation after being incubated with various micelles and concentrations. The error bars are based on the standard deviations of five parallel samples. (D) Fluorescence images of calcein AM/PI co-stained HeLa cells after incubation with PM, IM, and ICM upon being exposed to 808 nm laser at power density of 1 W cm-2 for 10 min (right side). Cells incubated with the same concentration (0.5 g/L) of polymeric micelles without laser irradiation were chosen as controls (left side).
Figure 4
(A) Time-lapse NIR fluorescence (NIRF) images in mice taken at different times after intravenous injection of PM or ICM (200 µL, 2.0 g/L). (B) NIRF intensities and contrast index (CI) values quantified at the indicated time points (Tumor/Muscle ratio). (C) NIRF images taken for tumor and normal organs [tumor (T), heart (H), liver (Li), spleen (S), lung (Lu), kidney (K)] and (D) the quantification of CI values 24 h after the intravenous injection of PM or ICM.
Figure 5
(A) PA images of ICM at different concentrations (g/L). (B) PA MAP images obtained for mice after intravenous injections of IR-780 micelles or PBS (C) PA intensity as a function of ICM at different concentrations. (D) Corresponding PA intensity of ICM and PBS buffer in tumor sites at different time points.
Figure 6
(A) In vivo NIR thermal imaging obtained 24 h after the intravenous injection of PM or ICM (200 µL, 2.0 g/L) into mice and treatment by an 808 nm laser at a power density of 1 W cm-2 for 10 min. (B) Temperature change at the tumor sites as a function of irradiation time. (C) Effects of photothermal therapy in HeLa tumor-bearing mice. Representative time-dependent photos taken for mice after being irradiated by 808 nm NIR light with ICM, IM, PM (200 µL, 2.0 g/L), and PBS post-injection. (D) Tumor volumes of different groups measured after laser irradiation and normalized to their initial size (n = 5 per group). Error bars indicated the means and standard errors.
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