Photothermal tumor ablation in mice with repeated therapy sessions using NIR-absorbing micellar hydrogels formed in situ
Introduction
Cancer is one of the leading causes of death. Radiotherapy and chemotherapy are the most commonly used methods for treating cancer [1], [2]. However, these treatments commonly cause systemic cytotoxicity owing to their non-specific drug delivery to all tissues, including healthy ones [3]. In recent years, minimally invasive approaches that use photothermal energy for the selective treatment of tumor cells have attracted much attention [4], [5]. Photothermal therapy (PTT) has the advantage over radiotherapy and chemotherapy of having fewer side-effects [6].
PTT uses inorganic nanomaterials [7], [8], [9], organic dyes [10], or nanoparticles of conductive polymers (such as polyaniline, PANI) [11], [12] that can strongly absorb near-infrared (NIR) laser light and effectively convert its light energy to localized heat for the photothermal ablation of tumor cells. However, these nanomaterials predominantly accumulate in the liver and spleen rather than the tumors when administered systematically [6], [13], [14]; additionally, they are typically nondegradable. Conversely, if implanted at the diseased site via local injection, most of these nanomaterials are susceptible to rapid clearance [15] because they are too small to be retained in the interstices of tissues [16], [17]. These issues potentially limit the photothermal efficacy of these nanosized PTT agents in clinical applications.
Recently, we developed an in situ-formed hydrogel of a chitosan (CS) derivative that contained self-doped PANI side-chains [18]. The self-doped PANI in the hydrogel effectively converted NIR light energy into localized heat in a mouse model with subcutaneous abscesses, resulting in the thermal lysis of bacteria and reparation of the infected wound with a single photothermal treatment.
Clinically, the treatment of a cancer must commonly be repeated because cancers are both aggressive and resistant [19], [20]. Owing to their rapid clearance in vivo, the aforementioned nanosized PTT agents may not be effective in repeated photothermal treatments. Therefore, a PTT material that can be retained at the diseased site and repeatedly activated by NIR light for localized tumor ablation is therefore urgently required.
This work further studies the feasibility of using the in situ-formed hydrogel of a CS derivative as an effective PTT agent in the repeated photothermal treatments of cancers. Hollow gold nanospheres (HGNs), an inorganic PTT agent [21], [22], [23], were used as a control. Fig. 1 schematically depicts the chemical structure of the synthesized CS derivative and the mechanism by which it photothermally treated Hep3B (a human hepatocellular carcinoma cell line) tumors that were created subcutaneously in a mouse model. The synthesized CS derivative was suspended in deionized (DI) water at pH 6.3 and injected intratumorally at the site of tumors to form hydrogels in a process that was driven by a local change in pH. The extracellular pH in the microenvironment of solid tumors is 6.9–7.0 [24], [25]. Hydrogels are three-dimensional polymeric networks which provides themselves spatial stabilization, avoiding the leakage into the neighboring tissues. An 808 nm NIR laser beam was focused on the tumor for 5 min during each treatment session, and the tumor temperature was maintained at 50–55 °C. This process was repeated every four days for a total of four treatment sessions.
The sol–gel transition of the CS derivative in an aqueous medium that can provide spatial stability in the microenvironment of a solid tumor was investigated using small-angle X-ray scattering (SAXS). The fundamental material characteristics of the aqueous solution of the CS derivative, including its optical properties, photothermal effect and stability, and cytotoxicity were examined in vitro. The effectiveness of its photothermal ablation of Hep3B cells was investigated. Finally, the in vivo biocompatibility and special stability of the in situ-formed hydrogel, as well as its NIR-mediated therapeutic efficacy during repeated treatment sessions, were evaluated in mice.
Section snippets
Materials
CS (viscosity 36 mPa s, 0.5% in 0.5% acetic acid at 20 °C) with approximately 85% deacetylation was purchased from Koyo Chemical Co. Ltd. (Tokyo, Japan). All other chemicals - aniline, ammonium persulfate (APS), hydrochloric acid (HCl), sodium hydroxide (NaOH), 1-methyl-2-pyrrolidinone (NMP), and 3-mercapto-1-propanesulfonic acid sodium salt (MPS-Na) - were obtained from Sigma–Aldrich (St Louis, MO, USA). Hep3B cells were obtained from the Bioresource Collection and Research Center, Food
Results and discussion
Recently, polymer solutions that can be transformed into hydrogels in situ as a result of changes in environmental stimuli have been extensively studied with a view to their use in the treatment of cancers [31], [32], [33]. The pH-sensitive polymer solution that was used in this work contained a CS derivative with self-doped PANI side-chains (NMPA-CS). The synthesized copolymers had been characterized in our previous publication [18].
Conclusions
The NMPA-CS micellar hydrogel formed herein can successfully and repeatedly convert NIR light into localized heat, and provides the PTT agent sufficient mechanical integrity to retain spatial stability in situ for a prolonged period. The animal study reveals the excellent tumor treatment efficacy of NMPA-CS micellar hydrogel without any significant toxic side-effects after multiple treatment sessions. This investigation establishes the feasibility of using the in situ-formed micellar hydrogel
Acknowledgments
This work was supported by a grant from the National Science Council (NSC 103-2221-E-007-022-MY3), Taiwan (ROC). The PET-imaging study was supported by grants from Chang Gung Memorial Hospital at Linkou (CMRPG300161 and CMRPG391513), Taiwan.
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