It is very important to decide what the best
It is very important to decide what the best time of NIR laser irradiation is for the optimized PTT. So the best way is to monitor the biodistribution of the nanoparticles in various tissues (specially, in tumors) temporally and spatially after iv injection. Based on the combined functions of therapy and diagnosis, theranostic nanoparticles are very fit for the individualized PTT. Here, our data showed the process of the nanoparticle biodistribution at 1–48 h after the administration by the optical imaging, indicating the gradually increased accumulation of our nanoparticles in EphB4-positive tumors at 1–24 h (Fig. 5A). As a result, the tumors were illuminated by NIR laser light for the optimized PTT at 24 h after iv injection of our nanoparticles in this work. So far, the antitumor efficacy in vivo of PTT has been mainly investigated in subcutaneous tumor model. More attention should be paid to PTT for the treatment of orthotopic and deeper tumors, which will be our next work.
Conclusions In this work, DTCSH, as theranostic nanoparticles with the integrated functions of optical imaging and photothermal conversion, was employed for the optimized PTT of tumors. Our data demonstrated the feasibility of increasing the accumulation of the nanoparticles into EphB4-positive tumors by the mediation between TNYL-peptide on the nanoparticles and EpHB4 on tumor cells, and used a double tumor mode in the same mice in vivo and a double tumor-cell co-culture strategy in the same well in vitro. Combined with NIR laser irradiation, our nanoparticles induced more death of EphB4-positive tumor 1,2-Dilauroyl-sn-glycerol in vitro than EphB4-negative tumor cells. We also developed optical imaging to monitor DTCSH biodistribution temporally and spatially. Obviously stronger antitumor efficacy of PTT against EphB4-positive tumors, compared with EphB4-negative tumors, was obtained under NIR laser irradiation at 24 h after DTCSH injection (iv), which was attributed to the enhanced accumulation of the nanoparticles in EphB4-positive tumors.
Acknowledgments This work was supported by the National Natural Science Foundation of China (81373348), the National Basic Research Program of China (973 Program) (2014CB744505), Major national science and technology projects, New Drug Creation of National 12th Five-Year Plan, No. 2011ZX09302-003-03, Qianjiang Talent Plan Program of Zhejiang Province (2013R10043) and the National Nature Science Foundation of China (81001411).
Introdution Cutaneous melanoma (primary site) is the most aggressive form of skin cancer, which is highly curable when localized to the primary site. However, when melanoma spreads to the regional lymph nodes, the 5-year survival rate is only 29% and once major organs are disseminated with disease the rate would fall to 7% (1). Alkylating agent dacarbazine usually was used as a standard treatment to treat metastatic melanoma, which frequently leads to poor outcomes, while combinations of chemotherapeutics have shown only marginally higher response rates, paying the price of systemic toxicity (2), (3). In addition, most patients with metastatic melanoma are incurable because of melanoma cells are generally insensitive to chemotherapy-induced cell death (3). Cisplatin is a neutral inorganic, square planar complex, which is one of the most potent anti-tumor agents. It exert cytotoxic effect by interaction with DNA to form DNA adducts, which culminate in either repair of the DNA damage and cell survival or activation of DNA damage-mediated apoptotic program. The clinical benefits of cisplatin as an anti-tumor agent have been recognized for over 30 years, which is also commonly used in the treatment of malignant melanoma (4). However, melanoma is relatively resistant to cisplatin even if it is highly effective in the treatment of many types of cancer (5). Despite some mechanisms of tumor resistance to cisplatin in other tumor types have been proposed in pre-clinical studies, the mechanisms of chemo-resistance are still unknown in melanoma. Possible explanations include disrupted accumulation of agents caused by drug pumps, up-regulated DNA repair, defective apoptosis signaling, and survival factor activation (6).