1. Introduction
Phototherapy has attracted extensive attention in recent years as a
powerful cancer treatment method due to their characteristics such as
convenience, noninvasiveness, locally selective treatment, negligible
drug resistance and minimized adverse side effect1.
Photodynamic therapy (PDT) and photothermal therapy (PTT) are two
typical phototherapy approaches, PTT is based on the photothermal agents
(PTA) which are preferentially taken up and retained by diseased tissue,
then after excitation by appropriate wavelength laser, the PTA convert
light to heat to induce cancer cells apoptosis or necrosis. Compare to
PDT, PTT is not affected by tumor microenvironment such as the local
oxygen level, so PTT have received increasing attention and develop
rapidly in recent years.
PTAs are one of the most important factors determining the efficiency of
PTT, many kinds of PTA have been developed in recent years. Current PTA
can be classified as inorganic and organic materials, compare to
inorganic PTA, the organic PTA with easy chemical structure tuning, good
biocompatibility, low-toxicity, and easy metabolism in biological system
are more desirable for clinical phototheranostics2-7,
such as cyanine days8-11, diketopyrrolopyrrole
derivatives12, 13, croconaine-based
agents14, 15, porphyrin-based
agents16-19, conjugated
polymers20-22, squaraine
derivatives23, 24, boron dipyrromethane (BODIPY)
dyes25 and so on. In organic PTAs, the polymeric PTA
was limited due to their complicated fabrication processes, indistinct
biodegradation, and potential biosafety19. So, the
small organic molecules have received increasing attention as potential
alternatives to nanomaterials in the area of PTT recently.
In addition, another main challenge for phototherapy is efficient treat
cancers at a deep tissue level. Near-infrared (NIR) light is referred to
as the “optical window” of the biological tissues due to the minimal
light absorption and scattering. Compared with the UV or visible light,
NIR shows larger penetration distance in tissue, lower photodamage
effect and higher signal-to-noise ratio 26,27. The organic molecules with extended π-conjugation
usually show strong NIR absorbance, which is beneficial for deep tumor
tissue diagnosis and phototherapy28-30. The well
designed conjugated small molecules organic PTA, especially recently
reported acceptor-donor-acceptor (A-D-A) structure PTAs would open a new
gate for efficient PTT of tumor in deep tissues 31-33.
However, a problem limiting the use of conjugated small molecules
organic PTA is their low water solubility, the hydrophobic PTA difficult
to prepare pharmaceutical formulations and cannot be directly injected
intravenously. To overcome these problems, various strategies have been
employed to prepare water-soluble and stable formulations of hydrophobic
organic PTA, such as conjugate to water-soluble
polymers11, loaded into mesoporous
materials17 or carbon
materials34-36, encapsulate in colloidal carriers such
as liposomes16, polymer
nanoparticles9, 10, 12, 13, 18-22, 25, 37, 38.
In this study, an A-D-A structure non-fullerene molecules, 3TT-IC-4Cl,
which includes three fused thieno[3,2-b]thiophene as the central
core and difluoro substituted indanone as the end groups was selected as
PTA for PTT. Similar with other A-D-A structure non-fullerene molecules,
3TT-IC-4Cl exhibits both broad absorption and effectively suppressed
fluorescence32, especially, 3TT-IC-4Cl exhibit strong
and broad absorption in 800-900 nm regions after forming nanoparticles,
it’s indicated that the 3TT-IC-4Cl has the potential as PTA for
NIR-triggered PTT of cancer in deep tissue. In order to effectively
utilize 3TT-IC-4Cl for PTT, herein, our previous reported folic acid
(FA) conjugated amphiphilic block copolymer (folic acid-polyethylene
glycol-poly (β-benzyl-L-aspartate)10,
FA-PEG-PBLA10) was employed to encapsulate 3TT-IC-4Cl by
nano-precipitation and dialysis process to form stable nanoparticles
(TNPs), and improve 3TT-IC-4Cl solubility in aqueous solution. In the
TNPs system, 3TT-IC-4Cl and PBLA segment of copolymer as inner core for
3TT-IC-4Cl storage, 3TT-IC-4Cl as the heat source, and PEG segment as
the out shell to improve solubility, stability and biocompatibility of
this system, active targeting ligand FA was introduced to the surface of
nanoparticles to enhance selectivity of nanoparticles.
Recently, the NIR-triggered organic small molecular based PTT system
have been developed9, 10, 12, 13, 17, 22, 25, 39,
however, few systems of A-D-A type small molecular organic PTA based and
880 nm triggered PTT have been reported.