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.