Repolarization of macrophages to improve sorafenib sensitivity for combination cancer therapy.

Sorafenib is the first line drug for hepatocellular carcinoma (HCC) therapy. However, HCC patients usually acquire resistance to sorafenib treatment within 6 months. Recent evidences have shown that anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues. Therefore, repolarization of TAMs phenotype could be expected to not only eliminate the influence of TAMs on sorafenib lethality to HCC cells, but also provide an additional anticancer effect to achieve combination therapy. However, immune side effects remain a great challenge due to the non-specific macrophage repolarization in normal tissues. We herein employed a tumor microenvironment (TME) pH-responsive nanoplatform to concurrently transport sorafenib and modified resiquimod (R848-C16). This nanoparticle (NP) platform is made with a TME pH-responsive methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymer. After intravenous administration, the co-delivery NPs could highly accumulate in the tumor tissues and then respond to the TME pH to detach their surface PEG chains. With this PEG detachment to enhance uptake by TAMs and HCC cells, the co-delivery NPs could combinatorially inhibit HCC tumor growth via sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs into tumoricidal M1-like macrophages. STATEMENT OF SIGNIFICANCE: Anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues to restrict the anticancer effect. In this work, we designed and developed a tumor microenvironment (TME) pH-responsive nanoplatform for systemic co-delivery of sorafenib and resiquimod in hepatocellular carcinoma (HCC) therapy. These co-delivery NPs show high tumor accumulation and could respond to the TME pH to enhance uptake by TAMs and HCC cells. With the sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs, the co-delivery NPs show a combinational inhibition of HCC tumor growth in both xenograft and orthotopic tumor models.

Fully Natural Lecithin Encapsulated Nano-Resveratrol for Anti-Cancer Therapy.

Introduction: Chemotherapeutics are known to have undesirable side effects (i.e. nausea, weight loss, hair loss, weakened immune system, etc.) due to the non-specificity of the drugs. Encapsulation of these chemotherapeutics inside nanoparticles significantly improves the bioavailability and half-life of drugs, while increasing their tumor penetration and localization. However, most, if not all, nanoparticles in clinics or research are synthetic, with no long-term studies on the effect of these nanoparticles in vivo. Herein, we developed a synergistic resveratrol nanoparticle system by using lecithin encapsulation. Lecithin, being a fully natural phospholipid derived from soybean, possesses inherent anti-tumor activity. Methods: Lec(RSV) was successfully prepared using the nanoprecipitation method, and characterized by particle size and zeta potential analysis, and transmission electron microscopy (TEM). The in vitro cellular uptake and cytotoxic effects of Lec(RSV) were investigated in human breast cancer cell line BT474. Finally, the in vivo tumoral uptake of Lec(RSV) was carried out in the BT474 orthotopic model. Results: Lec(RSV) showed a uniform distribution of ~120 nm, with prolonged stability. Lec(RSV) showed high cellular uptake and anti-cancer properties in vitro. Time-dependent uptake in the BT474 xenograft model indicated an increased tumoral uptake and apoptosis rate at 4 hours after tail vein injection of Lec(RSV). Conclusion: Taken together, we successfully developed a fully natural Lec(RSV) that possesses potent anti-cancer activity in vitro, with good tumoral uptake in vivo. We hypothesize that Lec(RSV) could be a safe anti-cancer therapeutic that could be easily translated into clinical application.

Fabrication of PEGylated Fe@Bi2S3 nanocomposites for dual-mode imaging and synergistic thermoradiotherapy.

Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.

Antimonene Quantum Dots: Synthesis and Application as Near-Infrared Photothermal Agents for Effective Cancer Therapy.

Photothermal therapy (PTT) has shown significant potential for cancer therapy. However, developing nanomaterials (NMs)-based photothermal agents (PTAs) with satisfactory photothermal conversion efficacy (PTCE) and biocompatibility remains a key challenge. Herein, a new generation of PTAs based on two-dimensional (2D) antimonene quantum dots (AMQDs) was developed by a novel liquid exfoliation method. Surface modification of AMQDs with polyethylene glycol (PEG) significantly enhanced both biocompatibility and stability in physiological medium. The PEG-coated AMQDs showed a PTCE of 45.5 %, which is higher than many other NMs-based PTAs such as graphene, Au, MoS2 , and black phosphorus (BP). The AMQDs-based PTAs also exhibited a unique feature of NIR-induced rapid degradability. Through both in vitro and in vivo studies, the PEG-coated AMQDs demonstrated notable NIR-induced tumor ablation ability. This work is expected to expand the utility of 2D antimonene (AM) to biomedical applications through the development of an entirely novel PTA platform.