An oxidation responsive nano-radiosensitizer increases radiotherapy efficacy by remolding tumor vasculature.

As an excellent candidate material for nano-sensitizers, gold nanostructures have shown great potential in radiotherapy. Nevertheless, severe hypoxia and low accumulation of nanomedicine caused by poor perfusion at the tumor site have significantly reduced radiotherapy efficacy. Vascular normalization has gained attention owing to its ability to relieve hypoxia and increase perfusion. The synergistic therapy of tumor vascular normalization and radiotherapy has become a new option to increase anti-cancer efficacy. However, the commonly used strategy of suppressing a single growth factor to induce vascular normalization is limited by tumor compensatory effects. In this work, we developed a strategy to inhibit oxidative stress in tumors by generating chelating agents in response to hydrogen peroxide, thereby inhibiting multi-angiogenic factors simultaneously to normalize blood vessels. Concretely, sodium alginate (SA) reacted with 8-quinoline boric acid (QBA) to form SA-QBA. Then gold nanoparticles (Au NPs) were modified with SA-QBA to obtain Au@SA-QBA. The system was simple in structure and could generate 8HQ in response to H2O2in vitro to inhibit oxidative stress and reduce the expression of VEGF, bFGF, and Ang-2. In vivo, the perfusion unit (PU) increased by 78% after Au@SA-QBA treatment, and the coverage of pericytes increased by 32%, which in turn induced vascular normalization. In addition, blood routine and blood biochemical tests confirmed its good biocompatibility and 8HQ was not detected in the supernatant after homogenization of major organs. More importantly, after the synergistic treatment of vascular normalization and radiotherapy (4 Gy), the tumor growth inhibition rate was increased by 38.6% compared to the Au@SA-treated group with negligible side effects to normal tissues.

In situ self-assembled biosupramolecular porphyrin nanofibers for enhancing photodynamic therapy in tumors.

Due to the complicated environment and high tissue hydraulic pressure in tumors that easily pumps the nanomedicines back to the systemic circulation, the concentration of released photosensitizers (PSs) retained in a tumor by a traditional nano-delivery system is very low, causing an unsatisfactory photodynamic therapy (PDT) effect. Therefore, we prepared a pH/H2O2-responsive nano-system (ZnP-OC-M) through modified porphyrin PS units with a long-unsaturated oleoyl chloride chain, and by the further introduction of hydrophilic hydroxyl groups and MnO2 through a cis-addition reaction between the unsaturated double bonds of oleoyl chloride and dilute KMnO4 solution. Making use of the sensitivity of MnO2 to the H2O2 in the acid environment of tumor cells, ZnP-OC-M selectively realized responsive disintegration and O2 generation. More importantly, the rich amphiphilic PS units were shedded simultaneously and spontaneously completed the self-assembly into nanofibers in situ by helical stacking, which displayed a 1.85-fold higher retention effect of PSs in vivo compared with free PS groups and showed a great tumor inhibition effect in enhancing PDT. This nanosystem effectively solves the problem of the low retention abilities leading to a poor PS concentration in a tumor, prolonging the treatment time window efficiently after only a single administration and achieving the purpose of PDT enhancement.

Zwitterionic chitooligosaccharide-modified ink-blue titanium dioxide nanoparticles with inherent immune activation for enhanced photothermal therapy.

Photothermal therapy (PTT) can trigger massive apoptosis of cancer cells, and this sharply increasing local apoptotic rate may recruit plenty of tumor-associated macrophages (TAMs). Although TAMs are recognized to display an M2-like subtype, which encourages tumor ontogenesis, they can be re-educated to a tumoricidal M1-like subtype by immunomodulatory reagents. Chitooligosaccharides (COSs) are endowed with immunomodulatory ability, but the positive electrical property limits their application; besides, their re-educating ability on TAMs is uncertain. Therefore, we proposed whether the combination of zwitterionic COS with a photothermal material can impair the undesirable tumor promotion of TAMs, thus enhancing the PTT treatment outcome. Herein, zwitterionic COS was obtained via the carboxymethylate method and then, the obtained COS was modified on the surface of ink-blue titanium dioxide (BTiO2) with photothermal ability to synthesize BTC NPs. In vitro, the immunofluorescence staining and cell survival assays indicated that BTC NPs could re-educate 87% of the M2-like RAW264.7 macrophages stimulated by apoptotic tumor cell secretion and significantly inhibit the liver tumor cell proliferation. Notably, in a mouse H22 liver cancer model, compared with mono PTT with BTiO2, the PTT treatment of BTC could reverse the ratio of M2 : M1 from 3.3 : 1 to 0.5 : 1, thus leading to 20.7% increase in the tumor inhibition rate. In general, our study demonstrated that zwitterionic COS can act as a potent immune activator to re-educate TAMs to M1. Furthermore, equipping the photothermal material with zwitterionic COS can be a potential treatment paradigm to achieve more forceful PTT.