br Modifying the surface of inorganic nanomaterials
Modifying the surface of inorganic nanomaterials with proper coating is essential for their biomedical applications. The surface coating can extend the blood circulation lifetime of nanoparticles, im-prove their biocompatibility and Ko 143 and prevent them from rapid clearance from the body . In the present study, we developed a Pharmacological Research 143 (2019) 178–185
nanocomposite hydrogel by incorporating AuNPs within the alginate hydrogel network. Alginate is a natural polysaccharide derived from brown algae, which has been widely utilized in drug delivery applica-tions because of its biocompatibility, biodegradability, hydrophilicity and mucoadhesive properties . Recent studies demonstrated that alginate coating of nanocarriers could prolong their blood circulation half-life, which in turn elevate the in vivo bioavailability of drug pay-loads in tumor tissue . On the other hand, previous studies have manifested that alginate coating of nanocarriers can enhance the cel-lular accumulation and retention of drugs, and more importantly fa-cilitates the nuclear drug delivery [42–44]. Indeed, these eﬀects might be the reasons why ACA nanocomplex exhibited a significantly higher chemotherapy eﬃcacy than free cisplatin as shown in this study.
The thermometry results support that ACA nanocomplex is able to transform laser light into heat, thanks to the surface plasmon resonance property of AuNPs. The tumors treated with ACA + laser showed an enhanced temperature elevation rate compared to laser irradiation alone, and reached to the thermal ablation range (> 45 °C), subse-quently receiving much higher thermal doses. Moreover, it is evident that the tumors treated with ACA + laser indicated a diﬀerential tem-perature rises and then received the higher thermal doses at the sub-sequent treatment sessions under similar treatment conditions (Fig. 3). Prior studies evaluating the way of distribution of AuNPs within the tumor microenvironment demonstrated that AuNPs generally tend to accumulate in perivascular regions [45,46]. We hypothesize that this perivascular localization of AuNPs mediates a vascular focused hy-perthermia upon laser irradiation and subsequently imparts thermal damages to the tumor vasculature. This may interrupt the tumor blood perfusion, thus preventing heat elimination from the tumor. In this condition, the tumor can reach to higher temperatures at the sub-sequent sessions of hyperthermia operation relative to the first treat-ment session, as observed in the present study (Fig. 3a). As a final outcome, it can be inferred that photothermal therapy provides a stronger therapeutic eﬃcacy at the subsequent treatment sessions which was proved according to the thermal dose analysis (Fig. 3b) where the mice treated with ACA + laser received dramatically higher thermal doses at S2 and S3 relative to S1.
It is well demonstrated that the cytotoxic eﬀect of many anticancer drugs such as platinum based drugs can be intensified at an elevated temperature . Several mechanisms have been reported to be re-sponsible for the synergistic interaction between heat and drug such as
(i) increased vascular permeability of the tumor which, in turn, en-hances the accumulation of drug within tumor tissue , (ii) delayed DNA-repair pathways at elevated temperatures, resulting in stabilizing DNA damage caused by anticancer drug , (iii) inhibited the activity of MDR transporter proteins at elevated temperatures and then pro-viding the potential of overcoming MDR . The as-prepared ACA nanocomplex in combination with laser irradiation can integrate dual therapeutic functions including photothermal therapy and che-motherapy simultaneously, thereby resulting in synergistic therapeutic eﬀects. The in vivo antitumor study proved that the combined chemo-photothermal therapy (ACA + Laser) resulted in the stronger ther-apeutic outcome than the separate application of photothermal therapy (AuNP + laser) and chemotherapy (ACA). Moreover, the tumor meta-bolism study revealed that this treatment strategy can eﬃciently era-dicate microscopic residual tumor, thereby preventing form tumor re-lapse. Consequently, the resulting product of this research will lead to achievement of a combinatorial synergistic cancer therapy strategy wherein heat and drug can be selectively deliver to the tumor.