Abstract
Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41−42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.
Highlights
Photodynamic therapy (PDT) has become a prominent therapeutic modality for cancer treatment [1–3]
We developed a multifunctional in situ-forming PEG-albumin hydrogel that was able to generate oxygen (O2 ) and singlet oxygen (1 O2 ) and emit moderate or severe heat for the combination treatment of hypoxic tumors using chemotherapeutic, photodynamic, and photothermal therapy
While PDT is a well-established technique that is commonly used clinically, is minimally invasive, and produces few side effects [39], Photothermal therapy (PTT) is used for two distinct purposes in practice: (i) independent treatment to suppress tumors by severe hyperthermia and (ii) supportive treatment to improve the delivery of chemotherapeutics and oxygen into tumors by increasing tumor blood flow due to moderate hyperthermia
Summary
Photodynamic therapy (PDT) has become a prominent therapeutic modality for cancer treatment [1–3]. PDT is based on the clinical use of reactive oxygen species (ROS). Such as singlet oxygen (1 O2 ) or hydroxyl radicals (OH) generated from oxygen (O2 ) using photosensitizers (PS) and light energy. The intracellularly generated ROS are able to damage cancer cells and tumor vasculature and induce immune-mediated tumor. The efficacy of many PDT and chemotherapeutic agents is seriously impaired by low oxygen concentrations within hypoxic tumors, which causes hypoxiainduced resistance of tumors to antitumor therapy [6]. Increasing the oxygen concentration in hypoxic tumors can be an effective method to overcome hypoxia-induced resistance of tumors to PDT [7–9]
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