Effect of Molecular Structure on Stability of Organic Nanoparticles

Subscriber access provided by CORNELL UNIVERSITY LIBRARY

Article

The effect of Molecular Structure on Stability of Organic Nanoparticles formed by Bodipy Dimers Wenhai Lin, Wei Zhang, Tingting Sun, Jingkai Gu, Zhigang Xie, and Xiabin Jing Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b02118 • Publication Date (Web): 29 Aug 2016 Downloaded from http://pubs.acs.org on August 29, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Langmuir is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

The effect of Molecular Structure on Stability of Organic Nanoparticles formed by Bodipy Dimers Wenhai Lin,†, ‡ Wei Zhang,†, ‡ Tingting Sun,†, ‡ Jingkai Gu,§ Zhigang Xie*,† and Xiabin Jing† †

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China ‡

University of Chinese Academy of Sciences, Beijing 100049, P. R. China

§

Research Center for Drug Metabolism, College of Life Sciences, Jilin University, Changchun

130012, P. R. China KEYWORDS: fluorescent nanoparticles, bodipy-dimer, passerini reaction, bioimaging, stability

ABSTRACT: The objective was to evaluate the stability of organic nanoparticles made from Bodipy dimers. Bodipy dimers with different length of linkers were synthesized via multicomponent Passerini reaction, and could form the fluorescent nanoparticles (FNPs) through nanoprecipitation. Bodipy-dimers FNPs with long chain linker indicated better stability in biological condition than those with short one as revealed by changes of diameter and size distribution. The FNPs possessed high physical homogeneity and low cytotoxicity. The molecular structure dependent stability was also validated by confocal laser scanning microscope

ACS Paragon Plus Environment

1

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 25

based on the dissociation-induced fluorescence recovering. Importantly, stable FNPs also could be used to load hydrophobic cargoes and delivery them into cytoplasm. We believe this systematic study between structure and stability might open new opportunities for designing stable nanoparticles for various applications.

1. INTRODUCTION Fluorescent nanoparticles (FNPs) attract much attention because of their extensive applications in imaging of live cells, chemosensing, and drug carriers.1-7 Relative to fluorescent dyes, FNPs show particular superiority, such as enhanced stability and pronounced cytocompatibility.8-13 Moreover, addition of targeting or drug molecules on the FNPs could facilitate their application in diagnostic and treatment of disease.14-17 Several strategies have been developed to fabricate nanostructures from the fluorescent dyes, including physical encapsulation or chemical modification.18-21 However, these methods usually need multistep or complicated procedures, and use of surfactants.22-24 It remains challenging to develop a simple and universal method for preparing FNPs from hydrophobic organic dyes. Self-assembly of organic molecules is a valuable method to prepare different nanostructures.25-28 For example, Zhang et al. reported the self-delivery nanoparticles from small molecular drug for cancer treatment.29 We reported a dual-responsive nanocapsule directly from hydrophobic fluorescent molecules.30 Actually, a pioneering work has been reported by Kasai et al. that the SN-38 drug dimer could form 50 nm particles in aqueous solution.31 After that, some small drug molecules were used to form nanomedicines without using any drug carriers or


2

Page 3 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

surfactants.32,33 We envisioned that the organic dye dimer also can self-assemble into nanoscale aggregates. 4-Difluoro-4-bora-3a,4a-diaza-s-indaacene (Bodipy) is a robust and hydrophobic organic dye.34 It is needful to develop a simple method to disperse them into aqueous solution. Recently, we have reported a stable fluorescent nanoparticle from pure Bodipy-dimer,13 but much more unknown need to be investigated. The relationship between molecular structure and physical properties of aggregates is not clear yet. For the further application in biology, it is necessary to understand the stability and compatibility of nanoparticles in physiological condition.35,36


3

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 25

Scheme 1. Synthesis of CxNBDP and a diagrammatic drawing of cellular uptake. In this work, we synthesized four Bodipy-dimers with different length of linkers through the multi-component Passerini reaction,37 and systematically studied their assembly behaviors in


4

Page 5 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

aqueous solution. The photophysical properties and stability of Bodipy-dimer FNPs were compared in vitro. These Bodipy-dimer FNPs indicated effective cellular uptake and low toxicity. Besides living cell bioimaging, Bodipy-dimer FNPs also could encapsulate Nile red as a model drug and delivery it into intracellular region (Scheme 1). 2. MATERIALS AND METHODS 2.1.

Materials.

4,4-Difluoro-8-(4-isocyanophenyl)-3,5-dimethyl-4-bora-3a,4a-diaza-s-

indacene (NC-BDP) was synthesized in the previous work.38 All reagents were purchased from commercial sources and used without further treatment, unless indicated otherwise. 2.2. Characterizations. Test methods and instruments were the same with our previous article.30 2.3. Synthesis of the CxNBDP. A mixture of NC-BDP (34.9 mg, 0.1 mmol), diacids (0.05 mmol) and o-nitrobenzaldehyde (15.1 mg, 3 mmol) in dichloromethane (CH2Cl2, 1 mL) was stirred at 25 oC for 4 days. Finally, the reaction mixture was chromatographed on a silica gel column (CH2Cl2:EtOAc = 10:1). 2.4. Preparation of CxNBDP NPs. The nano-precipitation method was used to prepare NPs. CxNBDP (2 mg) was dissolved in tetrahydrofuran (THF, 5 mL). We added dropwise the mixture into water, then stirred for several hours. The mixture was dialyzed to remove THF. 2.5. Preparation of the Nile red@C9NBDP NPs. C9NBDP (1 mg) and Nile red (0.1 mg) were dissolved in THF (5 mL). We added dropwise the mixture into water, then stirred for several hours. The mixture was dialyzed to remove THF. 2.6. Cellar uptake studies and cell viability assays. The detail experimental procedure and instruments were provided in our previous work.30, 39, 40 3. RESULTS AND DISCUSSION


5

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 25

3.1. Synthesis and characterization of CxNBDP NPs. Multi-component Passerini reaction is versatile to synthesize various functional molecules or polymers in mild conditions.41-43 The amphiphilic copolymers for curcumin carrier39 and cross-linked polymers with photocatalytic activity through Passerini reaction haven been reported.44 Herein, multi-component Passerini reaction was used to synthesize bodipy-dimers with different length of linkers (CxNBDP, C for carboxylic acid, x for the number of carbon atoms in diacids, N for o-nitrobenzaldehyde, BDP for Bodipy).

Figure 1. 1H NMR characterization of C8NBDP. 4,4-Difluoro-8-(4-isocyanophenyl)-3,5-dimethyl -4-bora-3a,4a-diaza-indacene (NC-BDP) was synthesized in previous work.38 Then NC-BDP, o-nitrobenzaldehyde and diacid were dissolved in CH2Cl2 and the mixture was stirred for 4 days. We obtained CxNBDP by column


6

Page 7 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

chromatography.

1

H

nuclear

magnetic

resonance

(NMR)

and

matrix-assisted

laser

desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used for structure characterization. C8NBDP for example, we could clearly resolve all the protons in the 1

H NMR spectrum in Figure 1, and the integration ratios of these peaks were consistent with

theoretical values. Furthermore, there were peaks standing for imide (8.57 ppm) and methane (6.76 ppm) protons indicated that C8NBDP was successfully synthesized. The m/z 1174.5 in MS was the theoretical molecular weight of C8NBDP (supporting information, Figure S1), which validate the structure of C8NBDP. Similar to C8NBDP, the structures of C4NBDP, C6NBDP and C9NBDP were confirmed (Figure S2, S3 and S4).


7

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 25

Figure 2. TEM images of (A) C4NBDP NPs, (B) C6NBDP NPs, (C) C8NBDP NPs and (D) C9NBDP NPs.

CxNBDP could self-assemble into nanoparticles (CxNBDP NPs) in aqueous solution through nanoprecipitation method. The hydrogen bond between amide linkages involved in the formation


8

Page 9 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

of nanoparticles according to FT-IR spectra (broad band at 3300-3330 cm-1 represent for hydrogen bonded N-H, Figure S5).45 Then CxNBDP NPs was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The TEM images demonstrated that all CxNBDP could self-assemble into spherical nanoparticles in aqueous solution (Figure 2). As the number of carbon atom in linkers increased, the average size of CxNBDP NPs increased from about 150 nm to 250 nm, except for C9NBDP NPs with size around 190 nm.

Figure 3. The diameter and PdI of (A) C4NBDP NPs, (B) C6NBDP NPs, (C) C8NBDP NPs and (D) C9NBDP NPs in PBS with FBS (10 %) measured by DLS. Colloidal stability was vital to their potential application. The changes of size and size distribution were monitored by DLS. The diameter and the polydispersity index (PdI) of all CxNBDP NPs almost remained unchanged in water over twenty days (Figure S6). These results


9

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 25

demonstrated that all CxNBDP NPs were stable in water. However, the changes of size and size distribution became quite different after incubating CxNBDP NPs in phosphate buffer solution (PBS, pH 7.4) containing fetal bovine serum (FBS, 10 %) at 37 oC. The PdI of C4NBDP NPs increased rapidly from 0.189 to 0.671 in 1.5 hours (Figure 3A), while the diameter and PdI of C6NBDP NPs were almost unchanged in 12 h but increased a lot in 24 h (Figure 3B). The diameter and PdI of C8NBDP NPs and C9NBDP NPs increased slightly in 24 h (Figure 3C and D). More intuitively, the inserted photos showed that a large number of micro-aggregates were found in the solution of C4NBBP NPs and C6NBDP NPs but the solution of C8NBDP NPs and C9NBDP NPs kept uniform in 24 h. These results indicated that the length of linkers had effect on the stability of corresponding NPs. Although all CxNBDP NPs could be stored in aqueous solution stably, BDP-dimers with long chain linkers indicated better stability than those with short linkers in PBS with 10% FBS. The increasing stability might be due to the increased hydrophobic interaction between the BDP and linkers, which has been seen in polymer system.46


10

Page 11 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 4. (A) UV-vis absorption and (B) fluorescence spectra of CxNBDP NPs in water and CxNBDP in MeOH.


11

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 25

We used photoluminescence emission and UV-vis absorption to characterize the optical properties of CxNBDP NPs. All CxNBDP in methanol (MeOH) exhibited the same absorption spectra with maximum absorption at 499 nm (Figure 4A). Compared to those of CxNBDP, the absorption spectra of CxNBDP NPs in water showed obvious red shifts, which peaked at 508, 510, 518 and 512 nm with the increase of the chain length. The bathochromic shift absorption band of CxNBDP NPs showed possible J-aggregates of CxNBDP NPs in water, which has been reported for gathering.30 The maximum emission wavelength centered around 515 nm for CxNBDP in MeOH (Figure 4B), but there was poor luminescence for CxNBDP NPs on account of aggregation-caused quenching (ACQ). The photo of CxNBDP and CxNBDP NPs irradiated under 365-nm light validated visually the phenomenon of ACQ.47 CxNBDP NPs in water emitted no fluorescence, while green fluorescence was observed for CxNBDP NPs in methanol (Figure S7). 3.2. Celluar uptake. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays were used to study the cytotoxicities of C6NBDP NPs, C8NBDP NPs and C9NBDP NPs towards human cervical carcinoma (HeLa) cells. C4NBDP NPs weren’t investigated because of the low stability of C4NBDP NPs in cell culture media. All CxNBDP NPs were biocompatible, and cell viability was over 80 % incubated with CxNBDP NPs at concentrations between 1 to 20 µg/mL for 24 (Figure S8).


12

Page 13 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 5. Representative CLSM images of HeLa cells after incubation with C9NBDP NPs for 1 and 3 h. Cell nuclei stained by DAPI (blue), C9NBDP fluorescence in cells (green), and overlays of both images were shown in picture from left to right for each panel. Scale bar, 50 µm. The cellular uptake of CxNBDP NPs in HeLa cells was evaluated by confocal laser scanning microscopy (CLSM). 4’,6-diamidino-2-phenylindole (DAPI) stained the cell nuclei (blue). Green fluorescence enhanced with time, which demonstrated that CxNBDP NPs could be endocytosed and emitted fluorescence (Figure 5, Figure S9 and S10).


13

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 25

Figure 6. Representative CLSM images of HeLa cells incubated with (A) C6NBDP NPs, (B) C8NBDP NPs and (C) C9NBDP NPs at the same concentration for 1 h. Cell nuclei stained by DAPI (blue), C9NBDP fluorescence in cells (green), and overlays of both images were shown in picture from left to right for each panel. Scale bar, 50 µm. (D) The CxNBDP fluorescence intensity in cells which are marked in red boxes.


14

Page 15 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

In order to compare the difference of cellular uptake, HeLa cells were incubated with C6NBDP NPs, C8NBDP NPs and C9NBDP NPs at the same concentration for 1 h, respectively. It was interesting the green fluorescence intensity of cells incubated with C8NBDP NPs was equal to that of C9NBDP NPs, but lower than that of C6NBDP NPs (Figure 6). The endocytosis of nanostructures was determined by several factors such as morphology, sizes, zeta potential.31 C6NBDP NPs, C8NBDP NPs and C9NBDP NPs showed similar zeta potential (Table S1, ~-30 mV) and spherical morphology. The sizes of C8NBDP NPs (~240nm) and C9NBDP NPs (~190 nm) did not affect the cellular uptake the similar fluorescence intensity (Figure 6B and 6C). Enhanced fluorescence of cells incubated with C6NBDP NPs (~210 nm) might result from the unstability of nanostrctures and fast disassembly in cellular media.

Figure 7. (A) Representative CLSM images of HeLa cells incubated with C9NBDP NPs for 1 h. Scale bar, 50 µm. HeLa cells were dyed by using DAPI and Lyso tracker red. (B) The trend of fluorescent intensity in a cell along the direction of the arrow marked in (A). The internalization of CxNBDP NPs was further investigated by colocalization experiments by using Lyso tracker red. C9NBDP NPs were chosen as an example. The green fluorescence from BDP and the red fluorescence from Lyso tracker red were matched well to form the yellow colocalization area, which indicated an accumulation of C9NBDP NPs in lysosomes (Figure 7A). The green and red fluorescence were coincident, which showed the good colocalization of C9NBDP NPs and lysosomes (Figure 7B).


15

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 25

3.3. Cargo loading and delivery. In order to demonstrate the potential of CxNBDP NPs as vehicles for cargo delivery, Nile red as a model drug was loaded into C9NBDP NPs. The content and concentration of Nile red were calculated to be 9.5 wt % and 5.2 µg/mL according to the UV-vis standard curve, respectively.

Figure 8. (A) The size and PdI of Nile red@C9NBDP NPs. (B) The TEM image of Nile red@C9NBDP NPs. (C) Representative CLSM images of HeLa cells incubated with Nile red@C9NBDP NPs for 1 h. The images from left to right show cell nucei by DAPI (blue), C9NBDP fluorescence (green), Nile red fluorescence (red) and overlays of three images above. Scale bar, 50 µm.


16

Page 17 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

DLS and TEM were used to characterize the size and morphology of Nile red@C9NBDP NPs. The average size of Nile red@C9NBDP NPs was 295.4 nm and PdI was 0.131 (Figure 8A). The diameter of Nile red@C9NBDP NPs was larger than that of C9NBDP NPs due to encapsulation of Nile red. The TEM image in Figure 8B showed a typical spherical nanostructure. The average diameter observed by TEM was consistent with that measured by DLS. The absorption and fluorencence bands of Nile red which peaked at 580 nm and 630 nm respectively were found in Figure S11 after evaluated by UV-vis spectrometry and photoluminescence spectra, which further confirmed the successful encapsulation of Nile red. The cellular uptake was evaluated in HeLa cells by CLSM (Figure 8C). The red fluorescence of Nile red was colocalized exactly with the green fluorescence of BDP. These results confirmed that C9NBDP NPs could encapsulate hydrophobic cargos (such as organic dyes and anticancer drugs) and transport them into cells. 4. CONCLUSIONS This work emphasizes the dimer-based self-assembly in the preparation of nanoparticles and the molecular structure dependent stability of nanoparticles. The dimer with long spacer will selfassemble into stable nano-aggregates in aqueous solution. The molecular structure can affect the stability of nanoparticles is not the particular case in this work. For example, the polymeric nanoparticles formed by monomers with longer chains exhibited better stability and slower release rates of their cargo.46 The podophyllotoxin dimer nanoparticle as another example validated the similar result. The cytotoxicity of nanoparticles increased as the length of the linker decreased, because the nanoparticles with short linker were unstable to release drug quickly.32 In a word, the structure-based stable nanoparticles significantly improve the potency of selfassembly of small molecules. Easy synthesis of nanoparticles from organic molecules provides new mechanistic insights into the rational design of nanomaterials.


17

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 25

ASSOCIATED CONTENT Supporting Information. MALDI-TOF MS spectrum of C8NBDP; 1H NMR characterization and MALDI-TOF MS spectra of C4NBDP, C6NBDP, C9NBDP; The diameter and PdI of CxNBDP NPs; Cell viability of HeLa cells incubated with CxNBDP NPs; FT-IR spectra of C8NBDP NPs and C9NBDP NPs freeze-dried; The photos of CxNBDP NPs in water and CxNBDP in MeOH under irradiation; Respresentative CLSM images of HeLa cells incubated with C6NBDP NPs and C8NBDP NPs; UV-vis absorption and fluorescence spectra of Nile red@C9NBDP NPs; Zeta potential of CxNBDP NPs. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Zhigang Xie E-mail: [email protected] Present Addresses State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences 5625 Renmin Street, Changchun, Jilin 130022, P. R. China ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Project No. 51522307 and 81430087).


18

Page 19 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

REFERENCES (1) Ma, D.-L.; He, H.-Z.; Leung, K.-H.; Chan, D. S.-H.; Leung, C.-H., Bioactive Luminescent Transition-Metal Complexes for Biomedical Applications. Angew. Chem. Int. Ed. 2013, 52, 7666-7682. (2) Zheng, M.; Ruan, S.; Liu, S.; Sun, T.; Qu, D.; Zhao, H.; Xie, Z.; Gao, H.; Jing, X.; Sun, Z., Self-Targeting Fluorescent Carbon Dots for Diagnosis of Brain Cancer Cells. ACS Nano 2015, 9, 11455-11461. (3) Weissleder, R.; Nahrendorf, M.; Pittet, M. J., Imaging Macrophages with Nanoparticles. Nat. Mater. 2014, 13, 125-138. (4) Li, J.; Cheng, F.; Huang, H.; Li, L.; Zhu, J. J., Nanomaterial-Based Activatable Imaging Probes: From Design to Biological Applications. Chem. Soc. Rev. 2015, 44, 7855-7880. (5) Li, K.; Liu, B., Polymer-Encapsulated Organic Nanoparticles for Fluorescence and Photoacoustic Imaging. Chem. Soc. Rev. 2014, 43, 6570-6597. (6) Liu, J.; Tian, X.; Luo, N.; Yang, C.; Xiao, J.; Shao, Y.; Chen, X.; Yang, G.; Chen, D.; Li, L. Sub-10 nm Monoclinic Gd2O3:Eu3+ Nanoparticles as Dual-Modal Nanoprobes for Magnetic Resonance and Fluorescence Imaging. Langmuir 2014, 30, 13005-13013. (7) Guo, R.; Zhang, L.; Qian, H.; Li, R.; Jiang, X.; Liu, B. Multifunctional Nanocarriers for Cell Imaging, Drug Delivery, and Near-IR Photothermal Therapy. Langmuir 2010, 26, 5428-5434. (8) Hu, R.; Leung, N. L.; Tang, B. Z., AIE Macromolecules: Syntheses, Structures and Functionalities. Chem. Soc. Rev. 2014, 43 , 4494-4562. (9) Chow, E. K.; Ho, D., Cancer nanomedicine: from drug delivery to imaging. Sci. Transl. Med. 2013, 5, 216rv4.


19

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 25

(10) Howard, M.; Zern, B. J.; Anselmo, A. C.; Shuvaev, V. V.; Mitragotri, S.; Muzykantov, V., Vascular Targeting of Nanocarriers: Perplexing Aspects of the Seemingly Straightforward Paradigm. ACS Nano 2014, 8, 4100-4132. (11) Howes, P. D.; Chandrawati, R.; Stevens, M. M., Colloidal Nanoparticles as Advanced Biological Sensors. Science 2014, 346, 1247390. (12) Quan, L.; Liu, S.; Sun, T.; Guan, X.; Lin, W.; Xie, Z.; Huang, Y.; Wang, Y.; Jing, X., NearInfrared Emitting Fluorescent BODIPY Nanovesicles for in Vivo Molecular Imaging and Drug Delivery. ACS Appl. Mater. Interfaces 2014, 6, 16166-16173. (13) Li, Z.; Zheng, M.; Guan, X.; Xie, Z.; Huang, Y.; Jing, X., Unadulterated BODIPY-Dimer Nanoparticles with High Stability and Good Biocompatibility for Cellular Imaging. Nanoscale 2014, 6, 5662-5665. (14) Zheng, M.; Liu, S.; Li, J.; Qu, D.; Zhao, H.; Guan, X.; Hu, X.; Xie, Z.; Jing, X.; Sun, Z., Integrating Oxaliplatin with Highly Luminescent Carbon Dots: An Unprecedented Theranostic Agent for Personalized Medicine. Adv. Mater. 2014, 26, 3554-3560. (15) Ng, K. K.; Zheng, G., Molecular Interactions in Organic Nanoparticles for Phototheranostic Applications. Chem. Rev. 2015, 115, 11012-11042. (16) Kunjachan, S.; Ehling, J.; Storm, G.; Kiessling, F.; Lammers, T., Noninvasive Imaging of Nanomedicines and Nanotheranostics: Principles, Progress, and Prospects. Chem. Rev. 2015, 115, 10907-10937. (17) Zhang, B.; Wang, X.; Liu, F.; Cheng, Y.; Shi, D. Effective Reduction of Nonspecific Binding by Surface Eengineering of Quantum Dots with Bovine Serum Albumin for CellTargeted Imaging. Langmuir 2012, 28 (48), 16605-16613.


20

Page 21 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

(18) Chen, Q.; Wang, C.; Zhan, Z.; He, W.; Cheng, Z.; Li, Y.; Liu, Z., Near-Infrared Dye Bound Albumin with Separated Imaging and Therapy Wavelength Channels for Imaging-Guided Photothermal Therapy. Biomaterials 2014, 35, 8206-8214. (19) Liu, J.; Yang, X.; Wang, K.; He, Y.; Zhang, P.; Ji, H.; Jian, L.; Liu, W. Single Nanoparticle Imaging and Characterization of Different Phospholipid-Encapsulated Quantum Dot Micelles. Langmuir 2012, 28, 10602-10609. (20) Li, S.; Shen, X.; Li, L.; Yuan, P.; Guan, Z.; Yao, S. Q.; Xu, Q. H. Conjugated-PolymerBased Red-Emitting Nanoparticles for Two-Photon Excitation Cell Imaging with High Contrast. Langmuir 2014, 30, 7623-7627. (21) Li, Q.; Zhang, J.; Sun, W.; Yu, J.; Wu, C.; Qin, W.; Chiu, D. T. Europium-ComplexGrafted Polymer Dots for Amplified Quenching and Cellular Imaging Applications. Langmuir 2014, 30, 8607-8614. (22) Shi, J.; Sun, X.; Li, J.; Man, H.; Shen, J.; Yu, Y.; Zhang, H., Multifunctional Near InfraredEmitting Long-Persistence Luminescent Nanoprobes for Drug Delivery and Targeted Tumor Imaging. Biomaterials 2015, 37, 260-270. (23) Mi, C.; Tian, Z.; Cao, C.; Wang, Z.; Mao, C.; Xu, S. Novel Microwave-Assisted Solvothermal Synthesis of NaYF4:Yb,Er Upconversion Nanoparticles and Their Application in Cancer Cell Imaging. Langmuir 2011, 27, 14632-14637. (24) Harrison, J.; Bartlett, C. A.; Cowin, G.; Nicholls, P. K.; Evans, C. W.; Clemons, T. D.; Zdyrko, B.; Luzinov, I. A.; Harvey, A. R.; Iyer, K. S.; Dunlop, S. A.; Fitzgerald, M., In Vivo Imaging and Biodistribution of Multimodal Polymeric Nanoparticles Delivered to the Optic Nerve. Small 2012, 8, 1579-1589.


21

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 25

(25) Yao, H.; Yamashita, M.; Kimura, K. Organic Styryl Dye Nanoparticles: Synthesis and Unique Spectroscopic Properties. Langmuir 2009, 25, 1131-1137.. (26) Yu, C.; Zhou, M.; Zhang, X.; Wei, W.; Chen, X.; Zhang, X., Smart Doxorubicin Nanoparticles with High Drug Payload for Enhanced Chemotherapy Against Drug Resistance and Cancer Diagnosis. Nanoscale 2015, 7, 5683-5690. (27) Zhang, J.; Li, S.; An, F. F.; Liu, J.; Jin, S.; Zhang, J. C.; Wang, P. C.; Zhang, X.; Lee, C. S.; Liang, X. J., Self-Carried Curcumin Nanoparticles for in Vitro and in Vivo Cancer Therapy with Real-Ttime Monitoring of Drug Release. Nanoscale 2015, 7, 13503-13510. (28) Zhang, W.; Lin, W.; Pei, Q.; Hu, X.; Xie, Z.; Jing, X. Redox-Hypersensitive Organic Nanoparticles for Selective Treatment of Cancer Cells. Chem. Mater. 2016, 28, 4440-4446. (29) Zhang, J.; Liang, Y.-C.; Lin, X.; Zhu, X.; Yan, L.; Li, S.; Yang, X.; Zhu, G.; Rogach, A. L.; Yu, P. K. N.; Shi, P.; Tu, L.-C.; Chang, C.-C.; Zhang, X.; Chen, X.; Zhang, W.; Lee, C.-S., Self-Monitoring and Self-Delivery of Photosensitizer-Doped Nanoparticles for Highly Effective Combination Cancer Therapy in Vitro and in Vivo. ACS Nano 2015, 9, 9741-9756. (30) Lin, W.; Sun, T.; Xie, Z.; Gu, J.; Jing, X., A Dual-Responsive Nanocapsule via DisulfideInduced Self-Assembly for Therapeutic Agent Delivery. Chem. Sci. 2016, 7, 1846-1852. (31) Kasai, H.; Murakami, T.; Ikuta, Y.; Koseki, Y.; Baba, K.; Oikawa, H.; Nakanishi, H.; Okada, M.; Shoji, M.; Ueda, M.; Imahori, H.; Hashida, M., Creation of Pure Nanodrugs and Their Anticancer Properties. Angew. Chem. Int. Ed. 2012, 51, 10315-10518. (32) Ikuta, Y.; Koseki, Y.; Onodera, T.; Oikawa, H.; Kasai, H., The Effect of Molecular Structure on the Anticancer Drug Release Rate from Prodrug Nanoparticles. Chem.Commun. 2015, 51,12835-12538.


22

Page 23 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

(33) Wang, H.; Xie, H.; Wang, J.; Wu, J.; Ma, X.; Li, L.; Wei, X.; Ling, Q.; Song, P.; Zhou, L.; Xu, X.; Zheng, S., Self-Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy. Adv. Funct. Mater. 2015, 25, 4956-4965. (34) Loudet, A.; Burgess, K., BODIPY Dyes and Their Derivatives: Syntheses and Spectroscopic Properties. Chem. Rev. 2007, 107 , 4891-4932. (35) Wang, W.; Ji, X.; Kapur, A.; Zhang, C.; Mattoussi, H., A Multifunctional Polymer Combining the Imidazole and Zwitterion Motifs as a Biocompatible Compact Coating for Quantum Dots. J. Am. Chem. Soc. 2015, 137, 14158-14172. (36) Liu, Y.; Purich, D. L.; Wu, C.; Wu, Y.; Chen, T.; Cui, C.; Zhang, L.; Cansiz, S.; Hou, W.; Wang, Y.; Yang, S.; Tan, W., Ionic Functionalization of Hydrophobic Colloidal Nanoparticles To Form Ionic Nanoparticles with Enzymelike Properties. J. Am. Chem. Soc. 2015, 137, 14952-14958. (37) Passerini, M. Isonitriles. II. Compounds with Aldehydes or with Ketones and Monobasic Organic Acids. Gazz. Chim. Ital. 1921, 51, 126-129. (38) Vazquez-Romero, A.; Kielland, N.; Arevalo, M. J.; Preciado, S.; Mellanby, R. J.; Feng, Y.; Lavilla, R.; Vendrell, M., Multicomponent Reactions for de Novo Synthesis of BODIPY Probes: In Vivo Imaging of Phagocytic Macrophages. J. Am. Chem. Soc. 2013, 135, 1601816021. (39) Lin, W.; Guan, X.; Sun, T.; Huang, Y.; Jing, X.; Xie, Z., Reduction-Sensitive Amphiphilic Copolymers Made via Multi-Component Passerini Reaction for Drug Delivery. Colloids Surf., B 2015, 126, 217-223.


23

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 25

(40) Sun, T.; Qi, J.; Zheng, M.; Xie, Z.; Wang, Z.; Jing, X. Thiadiazole Molecules and Poly(ethylene glycol)-Block-Polylactide Self-Assembled Nanoparticles as Effective Photothermal Agents. Colloids Surf., B 2015, 136, 201-206. (41) Dömling, A.; Wang, W.; Wang, K., Chemistry and Biology Of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083-3135. (42) Deng, X.-X.; Li, L.; Li, Z.-L.; Lv, A.; Du, F.-S.; Li, Z.-C., Sequence Regulated Poly(esteramide)s Based on Passerini Reaction. ACS Macro Lett. 2012, 1, 1300-1303. (43) Kakuchi,

R.;

Theato,

P.,

Three-Component

Reactions

for

Post-Polymerization

Modifications. ACS Macro Lett. 2013, 2, 419-422. (44) Lin, W.; Sun, T.; Zheng, M.; Xie, Z.; Huang, Y.; Jing, X., Synthesis of Cross-Linked Polymers via Mmulti-Component Passerini Reaction and Their Application as Efficient Photocatalysts. RSC Adv. 2014, 4, 25114-25117. (45) Gellman, S. H.; Dado, G. P.; Liang, G. B.; Adams, B. R. Conformation-Directing Effects of a Single Intramolecular Amide-Amide Hydrogen Bond: Variable-Temperature NMR and IR Studies on a Homologous Diamide Series. J. Am. Chem. Soc. 1991, 113, 1164-1173. (46) Wu, J.; Zhao, L.; Xu, X.; Bertrand, N.; Choi, W., II; Yameen, B.; Shi, J.; Shah, V.; Mulvale, M.; MacLean, J. L.; Farokhzad, O. C., Hydrophobic Cysteine Poly(disulfide)-Based RedoxHypersensitive Nanoparticle Platform for Cancer Theranostics. Angew. Chem. Int. Ed. 2015, 54, 9218-9223. (47) Ren, C.; Wang, H.; Mao, D.; Zhang, X.; Fengzhao, Q.; Shi, Y.; Ding, D.; Kong, D.; Wang, L.; Yang, Z., When Molecular Probes Meet Self-Assembly: An Enhanced Quenching Effect. Angew. Chem. Int. Ed. 2015, 54, 4823-4827.


24

Page 25 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Table of content

The effect of Molecular Structure on Stability of Organic Nanoparticles formed by Bodipy Dimers


25

Effect of Molecular Structure on Stability of Organic Nanoparticles

Recommend Documents