Cyclomatrix Polyphosphazene Porous Networks with J-Aggregated

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Cyclomatrix Polyphosphazene Porous Networks with J-Aggregated Multiphthalocyanine Arrays for Dual-Modality NIR Photosensitizers Jing Tan, Jittima Meeprasert, Yuxue Ding, Supawadee Namuangruk, Xuesong Ding, Changchun Wang, and Jia Guo ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b13594 • Publication Date (Web): 26 Oct 2018 Downloaded from http://pubs.acs.org on October 27, 2018

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ACS Applied Materials & Interfaces

Cyclomatrix Polyphosphazene Porous Networks with J-Aggregated Multiphthalocyanine Arrays for Dual-Modality NIR Photosensitizers Jing Tan,† Jittima Meeprasert,§ Yuxue Ding,† Supawadee Namuangruk, §

Xuesong Ding,*‡ Changchun Wang,† and Jia Guo*†

†State

Key Laboratory of Molecular Engineering of Polymers, and

Department of Macromolecular Science Fudan University, Shanghai 200433, P.R. China. ‡CAS

Key Laboratory of Nanosystem and Hierarchical Fabrication,

CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P.R. China. §National

Nanotechnology Center (NANOTEC), National Science and

Technology Development Agency, Pathumthani 12120, Thailand KEYWORDS. Conjugated porous polymers, Metallophthalocyanine, Near-infrared light, Polyphosphazene, Photothermal/photodynamic therapy

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ABSTRACT

Here, we have developed a kind of cyclomatrix polyphosphazene with

excellent

photophysical

potential of being organic

properties,

and

pursued

photosensitizers for

their

dual-modality

phototherapy. Briefly, hexachlorocyclophosphazene (HCCP) with D3h symmetry is adopted as a synthon to attach Zn(II) phthalocyanine (ZnPc) to form dendritic units that are covalently expanded into a soluble porous network through the nucleophilic substitution reaction. Molecular simulation reveals that the multi-ZnPc units around HCCP can be oriented in a side-by-side manner, leading to the remarkably red-shifted and intense absorbance in the nearinfrared

(NIR)

region.

To

validate

the

potential

in

bio-

application, such ZnPc-based polyphosphazenes are assembled by incorporation uniform

of

polyvinylpyrrolidone

nanoparticles

with

(PVP)

aqueous

to

produce

dispersibility

the and

biocompatibility. From the in vitro results, the PVP-stabilized photosensitizing

nanoparticles

photothermal/photodynamic

processes

can to

undergo

concurrently

the generate

heat and singlet oxygen for efficiently killing cancer cells upon exposure to a single-bandwidth NIR laser (785 nm). Compared with

the

known

organic

photosensitizers,

cyclomatrix

polyphosphazene would be a promising platform to configure a diversity

of

reticular

arrays

with

dense

and

oriented


2

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arrangement of dye molecules leading to their largely enhanced photophysical and photochemical properties.

1. INTRODUCTION Aggregates of organic dye molecules, which play an important role

in

systems,1

photobiological

have

recently

provoked

increasing interest for design of photosensitizing nanoplatforms for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively. One is termed face-to-face H-aggregates, which can cumulatively quenching

enhance

excited

interaction.

Thus

light

states the

absorptivity by

the

absorbed

and

remarkable

energy

is

induce π

self-

electronic

released

as

heat,

providing exceptional properties as PTT agents.2 Since singlet oxygen production requires intersystem crossing between oxygen and

excited

photosensitizers,

the

photodynamic

process

in

H-

aggregates is greatly inhibited and hamper their application in PDT.

Compared

with

the

former,

J-aggregation

is

molecularly

organized in a head-to-tail manner to form another type of noncovalent

assembles.3

photophysical

Such

properties

J-aggregates across

possess

long-wavelength

the

prominent

windows

with


3


Page 4 of 42

red-shifted, sharpened and intense optical absorption bands. The J-aggregates of organic dyes, such as porphyrin and indocyanine, have been explored as near-infrared (NIR) photosensitizers for PTT4,5 or PDT6 treatments with the high efficiency of photo-energy conversion, outperforming the performances of the corresponding H-aggregates in some recent reports.2,6 However, formation of Jaggregates has suffered from the specific molecular design and self-assembly for inhibition of prevailing H-aggregation. One of the solutions is incorporation of templates such as polymer,7,8 dendrimer,9 nanofilm,10 and micelles,11 to regulate the assembly of organic dye molecules in term of J-aggregation, while they are

highly

susceptible

to

change

in

the

surrounding

environment.12,13 The dynamic transition between aggregates and monomers may attenuate photophysical properties, leading to the less applicability in phototherapy.14 It is therefore proposed that J-aggregates are covalently immobilized on a platform to impart the stable and exceptional photosensitizing properties. As

reported

covalently

peptides15

recently,

attach

porphyrin

to

and

form

a

DNA16

are

enabled

side-by-side

to

assembled

array with J-aggregation interaction. In both cases, however, the

electronic

owing

to

the

coupling limited

interaction porphyrin

is

binding

typically sites

not

strong

available

in

platforms or the large distance between porphyrin binding sites. Therefore, a desirable platform, which can provide dense binding


4

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sites

and

enhanced

J-aggregation

interaction

for

covalently

attached chromphores, has remained to be well explored. Conjugated microporous polymers (CMPs) constitute a dominant class

of

amorphous

porous

organic

polymers

that

render

the

three-dimensional organic skeletons with permanent porosity and dense π-electronic conjugation.17,18 A variety of dye molecules such

as

pyrene,19-21

tetraphenylethene,22,23

porphyrin,26,27

perylene28

incorporated

to

photoelectric

and

design

Rose

CMPs

conversion,30,31

phthalocyanine,24,25 dye,29

Bengal as

have

been

photosensitizers

for

photocatalysis19,32-34

and

photodynamic therapy.35-38 The uniqueness of CMP structures lies in

that

a

number

of

closed

strained

rings

are

enforced

to

arrange the adjacent units by a coplanar manner, giving rise to the smaller torsion angles within closed rings for remarkably increased

conjugation.39

Therefore,

CMPs’

photophysical

properties such as light harvesting, long-wavelength absorption and

energy

transduction

outperform

the

analogous

linear

and

branched conjugated polymers. Soluble CMPs (SCMPs), which were designed to enhance branching degrees in microporous networks,21 are promising to be a desirable platform not only for solutionphase applications, but conceptually for development of higher functionality

through

the

integration

of

branching

moieties

within CMPs. With it in mind, we have envisioned the utilization of designable synthons to evolve the multi-arm dendritic arrays


5


of

dye

molecules

photophysical

into

properties

a

branched

resembles

CMP

Page 6 of 42

network,

J-aggregate

which

in

characters.

To

our knowledge, this is the innovative attempt to implementation of J-aggregation over the main scaffolds rather than among the side chains. As shown in Figure 1, a soluble polyphosphazene porous network is designed by using hexachlorocyclotriphosphazene (HCCP) as a synthon to react

with Zn(II) tetraamino-phthalocyanine (ZnPc)

through the nucleophilic substitution reaction of hexachloride and amine groups. HCCP is a well-known hexatopic core that has a nearly planar ring and six peripheral P–Cl bonds. The geminal substituents on the phosphorus atoms are oriented in a welldefined spatial arrangement, one above and one below the HCCP ring. The three substituents on either side of the HCCP ring are also mutually equidistant. As a result, covalent linkage of ZnPc on the six sites of one cyclic [NPCl2]3 could be contributed to the side-by-side alignment of adjacent ZnPc on a HCCP unit, and expands

into

cyclomatrix

a

branched

and

polyphosphazene.

cross-linked Although

network

HCCP-based

termed organic

frameworks have been reported,40 to the best of our knowledge, there

is

no

publication

yet

on

the

study

of

photophysical

properties of HCCP-based porous organic materials. Subsequently, the

aqueous

assembly

incorporation of

of

polyphosphazene


is

carried

out

by

(PVP), resulting in the


6

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hydrophobic outside

polyphosphazene

forming

a

corona.

in The

core

and

the

advantages

of

conjugated

PVP

polyphosphazene

nanoparticles stem not only from their improved applicability, but also from the prominent photophysical properties of HCCPlinked

multi-ZnPc

could

enhance

arrays

NIR

with

absorption

intrinsic and

J-aggregation,

which

photothermal/photodynamic

performances for concurrent generation of heat and toxic singlet oxygen

upon

exposure

to

a

single-bandwidth

NIR

laser.

Additionally, it is as well to prefer cyclophosphazanes owing to their inherent backbone degradability and biocompatibility.41

Figure 1. Preparation of PVP-stabilized SCMPs by the two steps: (i)

synthesis

of

SCMP(ZnPc)-HCCP

through

the

nucleophilic

substitution reaction of P-Cl bonds with amine groups, and (ii) aqueous assembly of SCMP(ZnPc)-HCCP into nanoparticles via PVP.

2. EXPERIMENTAL SECTION Materials: phenylene

Hexachlorocyclotriphosphazene diisocyanate

(PDI)

were

(HCCP)

purchased

and

from

1,4-

Aladdin


7


Chemicals.

1,

3,

Page 8 of 42

5-Benzenetricarboxaldehyde


(PVP,

Mw

=

10,000)

were

(TBA),

and

purchased

from

Energy Chemicals. Phosphate buffer saline (PBS), THF, ethanol, anhydrous DMF, triethylamine, and acetic acid were obtained from Shanghai Chemical Reagents Company. All reagents were purchased and

used

as

received.

Deionized

water

was

used

in

all

experiments. Zinc(II) tetraaminophthalocyanines [ZnPc(NH2)4] was synthesized by following our reported procedure.24 Synthesis

of

soluble

conjugated

microporous

polymers

(SCMP)

nanoparticles: The SCMP nanoparticles were prepared by the twostep method as described in the context. Typically, ZnPc(NH2)4 (10 mg, 0.015 mmol) and HCCP (7 mg, 0.02 mmol) were dissolved in anhydrous DMF (10 added

as catalyst.

mL), The

and trimethylamine (TEA, 768 reaction

mixture

was

μL)

degassed

was

by the

three freeze-pump-thaw cycles and then kept at 100oC for 24h. After the reaction, polyvinylpyrrolidone (PVP, 14 mg) was added to

complex

with

zinc

ions

of

SCMP(ZnPc)-HCCP.

The

resulting

solution was added dropwise (10 mL/h) into deionized water (40 mL) with ultra-sonication, and stirred at room temperature for additional

2

days.

centrifugation,

Afterwards,

washed

by

the

ethanol

product and

was

collected

deionized

water,

by and

freezing dried. Under otherwise identical conditions, CMP(ZnPc)TBA

and

reaction

CMP(ZnPc)-PDI of

TBA

and

were

PDI

with

prepared

by

ZnPc(NH2)4,

the

stoichiometric

respectively,

using


8

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acetic acid as catalyst. The two products were insoluble but could be stabilized by PVP to disperse in aqueous solution. Singlet (DPBF)

oxygen

was

generation

utilized

as

test:

1,

scavenger.

3-diphenylisobenzofuran

Samples

(100

μg/mL)

were

dispersed in the ethanol solution of DPBF (100 μM in 2.5 mL solution), and then the solutions transferred into a quartz cell in the dark. A 785-nm laser at the power of 1 W/cm2 irradiated the dispersions for 5 min, 10 min and 15 min, respectively, while

the

environmental

temperature

was

kept

at

25

oC.

Upon

switching off laser, the dispersion was centrifuged to collect supernatants, which was detected by UV-vis-NIR spectroscopy by using ethanol as reference. The absorption change of DPBF at 410 1O

nm was recorded to evaluate the investigate

the

effect

of

PTE

2

production level. In order to

on

PDE,

the

ethanol

solution

containing DPBF and SCMP nanoparticles was transferred into a quartz cell, which was placed in the sample tank of UV-vis-NIR spectrometer

attached

with

a

thermostatic

apparatus.

The

dispersion was irradiated by a 785-nm laser (1 W/cm2) for 2 min, 5 min and 8 min, and the system temperatures remained at 25 35

oC,

45

oC,

oC,

respectively.

Photothermal test: Typically, the PBS dispersion of samples (100 μg/mL, 300 μL) was placed in a 96-well plate and exposed to a 785-nm laser with a power of 1 W/cm2 for 7 min. The PBS solution

was

used

as

a

control.

The

temperature

change

was


9


Page 10 of 42

recorded with a thermocouple. To investigate the effect of PDE on

PTE,

capture

DPBF the

was

added

generated

as

scavenger

singlet

into

oxygen.

the

The

dispersion

other

to

measurement

conditions were remained. To calculate the photothermal conversion efficiency, the time constant method reported by Roper et al was adopted here.42 The solutions were exposed to the NIR laser for 7 min to reach a steady state with a maximum temperature. Then the laser switched off and the system cooled down to room temperature. The time constant for heat transfer was obtained from the cooling stage. The photothermal conversion efficiency is calculated from the energy balance when the system reaches a thermal equilibrium. From the data of cooling period, the time constant is determined to be τ = 96.2 s with the linear fitting method (see Figure S19 in the Supporting Information). In addition, the solvent mass m is 0.3 g and the heat capacity Cp is 4.2 J/(g

oC).

According to

the equation (1), hA is calculated to be 13.1 mW/°C. Thus the photothermal

conversion

efficiency

η

of

SCMP(ZnPc)-HCCP

nanoparticles can be calculated to be 47.0 % according equation (2).

hA 

η 

mC p

(1)

τ hA(Tmax - Tsurr ) - Qin,sol I

(2)


10

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In

vitro

cell

assay:

CCK-8

method

was

used

to

assess

the

viability of Hep G2 cells treated with samples. Cells were preseeded in a 96-well plate for 24 h and then incubated with samples of different concentrations (10, 20, 50, 100 and 200 μg/mL). Then NIR 785-nm laser at thepower of 1 W/cm2 or 2W/cm2 irradiated the cells for 5 min. The treated cells were cultured for

another

12

h under 37oC

within

5% CO2 atmosphere.

After

removing supernatant nutrient solution, the cells were incubated in 110 μL of DMEM containing 10 μL CCK-8 solution for 1 h. The absorbance of the suspension was measured at 450 nm on an ELISA reader. Cell viability was calculated by means of the following formula (3):

Cell viability 

OD( control )  OD( sample )  100% OD( control )

(3) Intracellular

1O

2

detection:

The

intracellular

generation

of

singlet oxygen was detected by fluorescence microscope, using dichlorfluorescein-diacetate (DCFH-DA) as probe. Hep G2 cells (2 mL, 2 × 105 cells per well) were seeded on a 6-well plate and cultured

for

nanoparticles.

24 After

h,

followed

24-h

by

incubation,

incubation the

culture

with medium

SCMP was

removed and the cells were stained with 1 mL of DCFH-DA (10 μmol/L) containing PBS at 37 °C for 30 min. A 785 nm laser (power density: 1 W/cm2, irradiation time: 5 min) was utilized to


11


Page 12 of 42

irradiate each well. Afterward, PBS solution containing DCFH-DA was

removed

and

rinsed

three

times

with

fresh

PBS.

Then

a

fluorescence microscope was used to visualize the intracellular 1O

2

generation. The green fluorescence of oxidized DCFH-DA was

observed at an excitation wavelength of 488 nm. Calculation: The models of HCCP-xZnPc are constructed by HCCP and ZnPc(NH2)4, wherein x in structures is varied by 1, 2, 4 and 6 to model the HCCP-ZnPc, HCCP-2ZnPc, HCCP-4ZnPc and HCCP-6ZnPc structures, respectively. The ground states of HCCP-xZnPc are fully

optimized

by

using

Density

Functional

Theory

(DFT)

at

B3LYP functional. The 6-31G(d,p) basis set is used for N, C, H, P and Cl atoms, and the LANL2DZ effective core potential is applied

to

excitation investigated

describe energy by

the

the

and

Zn

core

electronic

time

dependent

electrons.

The

absorption

spectrum

(TD)-DFT

with

vertical

the

are same

functional and basis set used for the ground state optimization. All calculations are performed by GAUSSIAN 09 program package. The detailed results are described in the Supporting Information (Figures S1-S11 and Tables S1-S6). Characterization: Morphological characterizations were carried out by using high-resolution transmission electron microscope (HR TEM) (JEOL 2100F, Japan), operated at 200 kV accelerating voltage at room temperature. The sample was prepared by dropcasting the ethanol dispersion onto a copper grid. Hydrodynamic


12

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diameter (Dh) measurement was conducted on a ZEN3600 (Malvern, UK) Zeta-sizer using a He-Ne laser at a wavelength of 632.8 nm. N2 adsorption-desorption isotherms were collected at 77 K by an ASAP2020

volumetric

adsorption

analyzer

(Micromeritics,

USA).

The samples were degassed at 120°C for 24 h before measurement. The UV-vis-NIR absorption spectra were collected on UV-vis-NIR Spectrophotometer Lambda 750 (Perkin-Elmer, USA). The samples was dissolved in THF at a concentration of 50 μg/mL or dispersed in PBS at a concentration of 100 μg/mL. FT IR spectra were recorded

on

Nicolet

transformation

6700

infrared

(Thermofisher,

spectrometer.

Samples

USA) were

Fourier dried

and

mixed with KBr to be compressed to a plate for measurement. Thermo-gravimetric

analysis

(TGA)

was

conducted

on

Pyris

1

Thermo Gravimetric Analyzer (PE, USA) at a heating rate of 20 oC/min

from 100

oC

to 800 oC under flowing air.

2. RESULTS AND DISCUSSION 2.1 Synthesis of PVP-stabilized SCMP nanoparticles Polymerization of ZnPc(NH2)4 monomers was carried out with HCCP in DMF at 100oC for 72h through the nucleophilic substitution reaction between terminal amine groups and P–Cl bonds with 1:1 stoichiometry, homogeneous

using

system

triethylamine remained

until

as

acid

the

acceptor.

reaction

The

halted,

indicative of the intrinsic solubility kept with increase of


13


molecular

weights

Information).

Then

(see PVP

Figure was

Page 14 of 42

S12

in

incorporated

the

into

Supporting

the

reaction

mixture for the conjugation with SCMPs through the interaction of pyrrolidone moieties with Zn(II) ions. With addition of PVPSCMPs

into

water,

the

supramolecular

assembly

occurred

by

arranging the hydrophobic SCMPs in core and the conjugated PVP outside forming a corona. The initially formed particles were then subjected to a ripening process at room temperature under mild stirring, affording the smooth surface and stable colloids by the continuous fusion and reorganization (see Figure S13 in the Supporting Information).

2.2 Characterizations


14

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Figure

2.

TEM

image

(a)

of

PVP-stabilized

SCMP(ZnPc)-HCCP

nanoparticles and their hydrodynamic diameter distribution (b) in

aqueous

solution.

Photographs

of

the

aqueous

dispersions

standing for 0h (c), 2h (d), 24h (e), and 7d (f), respectively, including: (1) PVP-stabilized SCMP(ZnPc)-HCCP, (2) SCMP(ZnPc)HCCP (12-h reaction), (3) SCMP(ZnPc)-HCCP (24-h reaction), (4) ZnPc(NH2)4, and (5) PVP-stabilized ZnPc(NH2)4. As

displayed

in

Figure

2a,

the

resulting

nanoparticles

are

uniformed in morphology and reach a narrow size distribution with the range of 50 nm to 100nm, as confirmed by SEM image again (see Figure S14 in the Supporting Information). The PVP encapsulation can constrain the excessive growth of particles


15


Page 16 of 42

and offer hydrophilicity. Dynamic light scattering measurement gives the hydrodynamic diameters of up to 200 nm with a small PDI of 0.2 (Figure 2b). It is larger than that observed by TEM due

largely

to the PVP

corona

swelling in

aqueous

solution.

Compared with the monomers and SCMPs without the stabilizers, the dispersion of PVP-coated SCMP nanoparticles remains stable in aqueous solution for over 7 days under ambient conditions (Figures 2c-2f).

Figure 3. FT IR spectra of HCCP, ZnPc(NH2)4, and PVP-stabilized SCMP(ZnPc)-HCCP. FT IR spectra in Figure 3 confirm the formation of -P-NHlinkages in the polymer network. In comparison to the building blocks, i.e. HCCP and ZnPc(NH2)4, the vibrations of P-Cl bonds at


16

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520 and 606 cm-1 disappear in product.43 Meanwhile, the double peaks of –NH2 groups at 3432 and 3358 cm-1 turn into a single band

at

3360

cm-1,

indicative

of

the

formation

of

secondary

amines (N-H) in the polymers. Besides the characteristic peak of endocyclic P=N bonds at 1143 cm-1, there are two of emerging peaks

at

1090

and

cm-1,

950

which

can

be

ascribed

to

the

asymmetric vibration of P-NH bond.40 Therefore, we confirm that the

polymerization

of

HCCP

and

ZnPc(NH2)4

occurs

through

the

formation of -P-NH- linkages. Additionally, the coordination of PVP with ZnPc units is also evidenced by the shift of C=O band from 1650 to 1683 cm-1 due to the coordination with metal ions. Thermo-gravimetric analysis of the product reveals the presence of ZnPc moiety, as there are 11.2 wt% of residues remaining until the temperature was up to 800oC at air atmosphere. They are assumed to be zinc oxide salts converted from ZnPc units, and therefore,

the

weight

percentage

of

ZnPc

in

the

SCMPs

is

calculated to be 87.8 wt% (see Figure S15 in the Supporting Information). SCMPs without addition of PVP precipitated out of water and were collected for porosity measurement by N2 sorption at 77K. A type-IV loops

sorption at

high

isotherm relative

is

observed

pressures

with

(see

slight

Figure

hysteresis

S16

in

the

Supporting Information). The surface area was evaluated by the Brunauer-Emmett-Teller model to give a moderate value of 118


17


Page 18 of 42

m2/g. The pore-size distribution is mainly populated around 2 nm and 20 nm, indicative of a hybrid of micro/mesopore character (inset in Figure S16). As reported by Cooper, SCMP is prone to form

the

hyperbranched

structure

rather

than

the

extended

network,21 so that the pore slits might be deformed as absorbers are condensed in. Also, we assume that they are crowded with numerous ZnPc units leading to the reduction of surface area. Appropriate

antisolvent

may

improve

the

porosity

because

the

tight packing of polymer chains can be suppressed during the precipitation, while the aqueous dispersion of SCMPs is required for bio-applications. Water thereby is a rational choice albeit with the sacrifice of partial surface areas of SCMPs.

2.3 NIR Absorption and Molecular Simulation


18

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Figure 4. (a) UV-vis-NIR spectra of ZnPc(NH2)4 and SCMP(ZnPc)HCCP

in

THF.

stabilized

(b)

Normalized

nanoparticles

concentration

of

100

in

absorbance aqueous

μg/mL.

(c)

of

different

solution

Solvothermal

at

PVP-

the

same

synthesis

of

CMP(ZnPc)-TBA and CMP(ZnPc)-PDI solids as control. Figure 4a displays the absorption of the resulting SCMPs in THF. An evident and broaden peak appears around 812 nm, which is red shifted by 100 nm in comparison to that of ZnPc(NH2)4. The enhanced NIR absorption definitely differs from those of CMP solids,

wherein

suspension.

the

Instead

light of

scattering

HCCP,

is

dominant

in

their

1,3,5-benzenetricarboxaldehyde

(TBA) and 1,4-phenylene diisocyanate (PDI) were solvothermally


19


Page 20 of 42

reacted with ZnPc(NH2)4 to synthesize the other two CMPs as a control,

denoted

as

CMP(ZnPc)-TBA

and

CMP(ZnPc)-PDI,

respectively (Figure 4c). They are insoluble in anything while could be stabilized by PVP in water (see Figure S17 in the Supporting Information). As the concentrations are all kept at 100 μg/mL in aqueous solution, SCMP(ZnPc)-HCCP shows the maximum NIR absorption at 785 nm, while the absorption of the other two CMPs both appear the weak shoulders without summit in the NIR region (Figure 4b). Note that both CMP(ZnPc)-PDI and CMP(ZnPc)TBA

anchor

the

ZnPc

units

on

the

nodes

of

the

crosslinking

networks with less correlation on each other. In the case of SCMP(ZnPc)-HCCP, the short distance between the neighboring ZnPc attached on one phosphorus of HCCP may allow for the formation of the side-to-side J-aggregation through the π-π interaction.


20

Page 21 of 42 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


Figure 5. The optimized top-view and side-view structures of trans-form HCCP-2ZnPc (a),

cis-form

HCCP-2ZnPc

(b), stacking-

form HCCP-2ZnPc (c), HCCP-4ZnPc (d) and HCCP-6ZnPc models (e,f).

To validate the assumption, we have performed the theoretical prediction of geometries and electronic properties on the xZnPcsubstituted Supporting

HCCP

ensembles

Information).

(see

calculated

Calculations

on

the

details

in

HCCP-ZnPc

the model

reveal its characteristic absorption around 370 nm, 430 nm and 630

nm.

molecular

All

of

electron

orbitals

(HOMOs)

densities and

of

lowest

the

highest

unoccupied

occupied molecular


21


Page 22 of 42

orbitals (LUMOs) are delocalized only on ZnPc moiety, and HCCP is

photochemically

inert

and

doesn’t

have

any

low

energy

absorption band of its own.44 For the HCCP-2ZnPc models (Figures 5a-5c), the three different conformations are optimized, i.e. trans-, cis-, and stacking-forms, wherein two of ZnPc units are linked

to

one

or

two

phosphorous

atoms,

respectively.

The

spectra of cis- and trans-forms show the analogous absorption bands, which are attributed to the electron transfer from one to the other ZnPc through the HCCP core during excitation. In the case of stacking form, the two ZnPc units are stacked by a partially staggered manner with the near distance of 3.49 Å and a slight increase of N-P bonds by 0.01 Å. As shown in Figure 6, there is an emerging broad absorption around 720 nm, which may account for the electron transfer within a pair of ZnPc units through their interacted orbitals. The result implies that the stacking-form ZnPc pair on a HCCP has an absorption character of J-aggregated

chromophores.

As

the

amine

group

of

ZnPc(NH2)4

alters the substituting position on the phenyl group, the isomer of HCCP-2ZnPc can also give the similar stacking form as well as red-shifted

absorption

(See

Figure

S18

and

Table

S7

in

the

Supporting Information). For the stacking forms of HCCP-4ZnPc and HCCP-6ZnPc (Figures 5d-5f), there exhibit the similar NIR absorptions in the range of 700-780 nm, but the intensity is much higher because the ZnPc pairs around one HCCP are more


22

Page 23 of 42 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


dense (Figure 6). Taken together, the calculations reveal that the

HCCP

adjacent

platform ZnPc

decides

units,

and

the hence,

J-aggregated the

arrangement

extended

of

π-conjugation

results in the red-shifted and enhanced absorption in the NIR window. The conclusion is well consistent with the experimental observations as obtained in Figure 4a and 4b.

Figure

6.

The

simulated

absorption

spectra

of

HCCP-ZnPc,

stacking-form HCCP-2ZnPc, HCCP-4ZnPc and HCCP-6ZnPc in the NIR window.

2.4 Photodynamic and photothermal effects Aside

from

transduction

the

NIR

absorption

of

PVP-stabilized

ability, SCMPs

in

the PBS

photo-energy has

been


23


Page 24 of 42

investigated upon irradiation of a 785-nm NIR laser at the power of 1 W/cm2. As displayed in Figure 7a, the temperature of aqueous dispersion increases significantly from 28oC to 58oC in 7 min until

the

system

remains

steady.

Subjected

to

the

same

treatment, less heat is generated in the presence of the other two CMPs. The photothermal conversion efficiency was estimated from the heating-cooling cycle by the time constant method (see Figure

S19

in

the

Supporting

Information).

The

photothermal

efficiencies of SCMP(ZnPc)-HCCP, CMP(ZnPc)-TBA and CMP(ZnPc)-PDI are

calculated

to

be

47.0%,

respectively

(Figure

7b).

photothermal

materials

As

(see

29.1%

and

compared Table

Information),

it

is

undoubted

nanoparticles

can

be

ranked

18.8% to

S8

that

among

in

the the

at

785

other

known

Supporting

PVP-stabilized the

best

nm,

of

SCMP

organic

photosensitizers.


24

Page 25 of 42 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


Figure 7. (a) Photothermal heating of the aqueous dispersions of three PVP-stabilized nanoparticles (0.1 mg/mL) irradiated by an 785-nm NIR laser for 7 min at 1 W/cm2 power (laser off time: 7 min).

(b)

Comparison

of

the

elevated

temperatures

and

photothermal efficiencies of the three CMPs with PBS as negative control. (c) Time-dependent absorbance change of DPBF in the presence of SCMP(ZnPc)-HCCP upon exposure to 1 W/cm2 power of 785-nm laser for 15 min (in ethanol). (d) Comparison of the decay rate of DPBF alone and in the presence of SCMP(ZnPc)-HCCP, CMP(ZnPc)-PDI, and CMP(ZnPc)-TBA, respectively.


25


Page 26 of 42

Generation of reactive oxygen species (ROS) by the excited ZnPc has been well known,45 while singlet oxygen production that is accompanied by heat generation has attracted our concern upon exposure of a single-bandwidth laser. 1,3-Diphenylisobenzofuran (DPBF)

was

utilized

as

ROS scavenger,

and its absorbance

in

ethanol was recorded by UV-vis spectroscopy at an interval of 5 min,

10

min

absorbance

and

15

min.

410

nm

is

at

A

significant

observed

in

the

decrease

of

DPBF

presence

of

SCMP

nanoparticles at a concentration of 0.1 mg/mL (Figure 7c). As a control, there is a negligible absorbance fall for DPBF used alone (see Figure S20 in the Supporting Information). Figure 7d depicts a function of DPBF absorbance at 410 nm against NIR illumination time for the different samples. As indicated from the

decay

level

of

property

rate ROS.

of

multi-ZnPc

of

DPBF,

We

believe

SCMP

has

arrays,

a

SCMP(ZnPc)-HCTP that

strong

resulting

the

generates

prominent

correlation in

the

with

a

maximum

photochemical a

number

photodynamic

of

process

intensified by the enhanced electron transfer.

2.5 In vitro test The early reported photosensitizers with PDT/PTT dual-modality have been usually configured with two kinds of materials that could

be activated by

a single-bandwidth laser.46,47 Recently,

exploration of single-component forming nanomaterials with the


26

Page 27 of 42 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


multimodal

potential

in

phototherapy

and

imaging

has

been

reported as well. For example, Zheng et al. developed a kind of nanovesicle

self-assembled

from

porphyrin

lipids,

as

termed

“porphysome”, to accomplish the structure-dependent activatable PTT/PDT utility.48 Here, we also find that SCMP(ZnPc)-HCCP alone can simultaneously generate heat and singlet oxygen through the conversion of single-bandwidth NIR-light energy. Thus the mutual impact

between

PDT

and

correlation

during

the

temperatures

are

different

PTT

studied

excitation.

maintained,

temperatures

was

is

the

nearly

As

level

to

discover

the

of

comparable

their

environmental

ROS

generated

with

each

at

other.

Also, in the presence of DPBF, the similar tendency of elevating temperatures has preserved (see Figure S21 in the Supporting Information). The results come to a conclusion that the PDT and PTT

are

relatively

independent

to

translate

the

NIR

light

energy. We reason that one part of absorbed energy is dissipated as heat through the vibration of conjugated skeletons, and the other would excite ZnPc units to take part in the photochemical reaction with oxygen. In light of the PDT/PTT performances, aqueous dispersibility and

appropriate

SCMP(ZnPc)-HCCP

sizes, as

a

we

were

photosensitizing

encouraged probe

for

to

envision

non-invasive

phototherapy (Figure 8a). Cell viability was evaluated in vitro by

CCK-8 assay for Hep

G2

cells treated with PVP-stabilized


27


Page 28 of 42

SCMP(ZnPc)-HCCP nanoparticles. As shown in Figure 8b, the agent itself

is

non-cytotoxic

while

can

induce

cellular

apoptosis

followed by 785-nm laser illumination for 5 min at 1 W/cm2 power. The inhibitory rate reaches approximately 50% at the dose of as low as 20 μg/mL. With a further increase of concentration (50 μg/mL), the viability can decrease to less than 10%. The rising power of NIR laser (2 W/cm2) also noticeably suppresses the cell viability. To estimate the contribution of PTT and PDT in cell apoptosis, respectively, N-acetylcysteine (NAC)

is applied

to

serve as ROS scavenger to make the PDT silent during the laser irradiation, so that the PTT is dominantly responsible for the cell damage. In this case, the cell survival rate was observed to be 17% presumably owing to the local generation of heat for cell apoptosis. As compared to the case without NAC, the SCMPtreated cells remain 7% viability, which is a result of PTT/PDT cooperative

treatment

(see

Figure

S22

in

the

Supporting

Information). As oxygen is deficient in Hep G2 cells, it is understandable that the effectiveness of PTT is more remarkable than PDT in the hypoxic system. In order to further validate the intracellular

1O

2

production,

dichlorfluorescein diacetate probe was employed to detect the Hep

G2

cells

incubated

with

the

PVP-stabilized

SCMPs.

As

displayed in Figures 8c-8e, the brilliant green fluorescence is emitted from the SCMP-treated cells upon exposure to NIR light,


28

Page 29 of 42 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


proving the abundant

1O

2

production in this case. Without light

illumination, the cells with and without treatment of SCMPs both have much less that

if

1O

2

accumulated within the cells. We emphasize

deficiency

of

intracellular

oxygen

elicits

the

attenuation of PDT, cancer cells still can be damaged by the thermal ablation pathway due to the presence of PTT.

Figure 8. (a) Schematic illustration of concurrent generation of heat and singlet oxygen on SCMP(ZnPc)-HCCP upon irradiation of 785-nm NIR laser. (b) Cell viability of Hep G2 cells in the presence of varying concentrations of PVP-stabilized SCMP(ZnPc)HCCP nanoparticles without (black) or with irradiation of 1 W/cm2 (red) and 2 W/cm2 power of 785-nm NIR laser, respectively (mean ± s.d., n = 3). (c-e) Fluorescence images of Hep G2 cells without


29


Page 30 of 42

any treatment (c), and treated by PVP-stabilized SCMP(ZnPc)-HCCP (0.1 mg/mL) without (d) and with (e) irradiation of 785-nm laser (1 W/cm2, 5 min). Scale bar: 10 µm.

3. CONCLUSIONS In

summary,

we

have

developed

an

innovative

approach

to

assembly of SCMPs into bio-available nanoparticles for potential NIR phototherapy. To enhance the π-conjugation, the D3h symmetric HCCP

linked

with

multiple

ZnPc

units

cyclomatrix polyphosphazene with the around

HCCP

as

photoactive

to

evolve

into

porous

J-type ZnPc aggregations

centers,

which

is

therefore

advantageous in term of the opening pores, prominent solubility and

enormous

absorption

implementation

of

the

in

the

NIR

region,

NIR-triggered

hybrid

and

enables

photophysical

process, i.e. PDT and PTT. Because of these features, we have engineered the SCMPs into biocompatible and aqueous-dispersible nanoparticles by the PVP-induced assembly method. The obtained nanoparticles feature remarkable stability, narrow particle-size distribution, non-cytotoxicity, and outstanding PTT/PDT efficacy upon exposure to a 785-nm NIR laser. Thus they can serve as photosensitizers

to

greatly

inhibit

the

proliferation

and

apoptosis of cancer cells with low doses and at a low power density. Given the structural diversity and flexibility of CMPs,


30

Page 31 of 42 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


we

anticipate

the

photosensitizing

advent

CMPs,

of

which

an

exciting

would

field

significantly

in

designing

improve

the

potential of CMPs for diagnosis and treatment of diseases.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: Detailed calculation methods and results, GPC curves, TEM images, SEM images, TGA curves, N2 sorption isotherm and poresize distribution, photothermal efficiency calculation, UV-visNIR spectra and cell viability estimation (PDF).

AUTHOR INFORMATION Corresponding Author *(J.G.) E-mail: [email protected], *(X.D.) E-mail: [email protected] Notes Any additional relevant notes should be placed here.

ACKNOWLEDGMENT


31


Page 32 of 42

This work is supported by NSFC (Grant Nos. 21474015, 21674026 and 21805043),

STCSM

(Grant

No.

14ZR1402300),

and

the

State

Key

Project of Research and Development (Grant No. 2016YFC1100300).

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Cyclomatrix Polyphosphazene Porous Networks with J-Aggregated

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