Leung Chan

Designing Core–Shell Gold and Selenium Nanocomposites for Cancer Radiochemotherapy

Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.

Construction of a cancer-targeted nanosystem as a payload of iron complexes to reverse cancer multidrug resistance

Multidrug resistance has been identified as a major cause of failure of cancer treatment. Due to their relative non-toxicity, selenium nanoparticles (SeNPs) have been reported as excellent cancer therapeutic nanodrugs. In this study, we designed and prepared a novel nanosystem with borneol surface-functionalized and liver targeting to overcome the multidrug resistance. Borneol (Bor)-modified SeNPs can significantly improve the stability of SeNPs and their anticancer activity. Fe(PiP)3 (PiP = 2-phenylimidazo [4,5-f][1,10] phenanthroline) is a novel anticancer agent with low solubility and stability. In this study, we have constructed a functionalized SeNPs (GAL/Bor@SeNPs) by the surface decoration of galactosamine (GAL), which is a liver targeting ligand that significantly enhanced the cellular uptake of Fe(PiP)3-loaded nanosystem via dynamin-mediated lipid raft endocytosis and clathrin-mediated endocytosis in liver cancer cells overexpressing asialoglycoprotein receptor, thus achieving amplified anticancer efficacy. This multifunctional nanosystem exhibited excellent hemocompatibility and anticancer activity comparing with Fe(PiP)3 or SeNPs alone. Remarkably, GAL/Bor@SeNPs antagonized the multidrug resistance in R-HepG2 cells by inhibiting the expression of ABC family proteins, resulting in enhanced drug accumulation and retention. Internalized nanoparticles released free iron complexes into the cytoplasm, which triggered ROS down-regulation and induced apoptosis through activating AKT and MAPKs pathways. Moreover, this nanosystem effectively prolonged the circulation time of encapsulated drugs. Taken together, this study suggests that GAL and Bor functionalization could be an effective strategy to design cancer-targeted nanomaterials to antagonize multidrug resistance in cancers.

Cancer-targeted tri-block copolymer nanoparticles as payloads of metal complexes to achieve enhanced cancer theranosis

Cancer targeting delivery and controlled release of metal complexes may offer a new approach to improve their anticancer efficacy with eliminated systemic toxicities. Herein, a biotin-conjugated tri-block polymer delivery system was designed and used as a carrier of potent ruthenium polypyridyl (RuPOP) complexes to achieve superior biocompatibility, higher water solubility and cancer-targeting ability. Biotin was used as a targeting molecule to enhance the cellular uptake and retention of RuPOP in diverse carcinoma cells. Furthermore, the nanosystem (Bio-PLGA@Ru) was efficiently internalized by cancer cells by the lipid raft-mediated endocytosis pathway, triggered ROS overproduction and activated p53-mediated apoptosis in cancer cells. Moreover, the nanosystem effectively accumulated in tumor tissue and alleviated the damage of the metal complex to the organs. Taken together, this study demonstrates a smart strategy for the fabrication of a biocompatible and cancer-targeted PLGA-based copolymer nanosystem to achieve superior tumor cell localization and anticancer ability with eliminated systemic toxicities.

Facile Fabrication of Near-Infrared Responsive and Chitosan-functionalized Cu2Se Nanoparticles for Cancer Photothermal Therapy

Photothermal therapy has attracted much interest for use in cancer treatment in recent years. In this study, Cu2 Se nanoparticles as a novel photothermal agent modified by chitosan (CS-Cu2 SeNPs) were successfully synthesized through a facile route at room temperature. The as-synthesized CS-Cu2 SeNPs exhibited good water solubility and significant stability. CS-Cu2 SeNPs can efficiently convert near-infrared (NIR) light into heat and exhibit excellent thermostability. In vitro experiments showed that CS-Cu2 SeNPs had selective cellular uptake between cancer and normal cells and expressed clear anticancer activity on A375 and HeLa human cancer cells. In addition, the anticancer activity was increased to about 400 % by combination with a laser at 808 nm, which acted through induction of apoptosis with the involvement of intrinsic and extrinsic pathways. CS-Cu2 SeNPs irradiated with a laser effectively triggered the intracellular reactive oxygen species (ROS) overproduction that promoted cell apoptosis. Therefore, the developed CS-Cu2 SeNPs could be used as a novel phototherapeutic agent for the photothermal therapy of human cancers.

Phycocyanin-based nanocarrier as a new nanoplatform for efficient overcoming of cancer drug resistance

Resistance to chemotherapy remains the primary obstacle for the successful treatment of cancers. Nanotechnology-based studies have developed many smart nanomedicines and efficient strategies to overcome multidrug resistance (MDR), which have brought new horizons to cancer therapy. Among them, protein-based nanomedicine represents an appealing drug delivery platform to realize safe and superior therapeutic effects due to its paramount biocompatibility with minimized toxicity. Herein we describe the rational design and construction of a novel protein-based nanocarrier using the naturally-occurring protein phycocyanin (PC) as the base material, to achieve safe and tumor-specific drug delivery. This cancer-targeting nanosystem (FA-PCNP@DOX) with bio-responsive properties exhibits positive targeting accumulation in resistant cancer cells and overcomes drug efflux by enhancing cellular uptake and retention time. Specifically, FA-PCNP@DOX inhibits the function of pumping proteins of the ABC family and triggers ROS-mediated apoptotic signaling pathways, thereby attaining highly efficient anticancer efficacy and overcoming drug resistance. Pharmaceutical studies demonstrate that FA-PCNP@DOX overwhelms DOX by sustained release in the blood, which verifies its prolonged circulation in vivo. Moreover, FA-PCNP@DOX efficiently accumulates in tumors and strengthens the tumor inhibitory effect of DOX by enhanced tumoral penetration. Importantly, FA-PCNP@DOX effectively reduces the hepatic, pulmonary, renal and cardiac toxicity caused by DOX. Therefore, as a new nanocarrier, this novel nanosystem could be further exploited as a safe and versatile nanoplatform for next-generation cancer therapy.

Transferrin-functionalized nanographene oxide for delivery of platinum complexes to enhance cancer-cell selectivity and apoptosis-inducing efficacy

Rational design and construction of delivery nanosystems for anticancer metal complexes is a crucial strategy to improve solubility under physiological conditions and permeability and retention behavior in tumor cells. Therefore, in this study, we designed and synthesize a transferrin (Tf)-conjugated nanographene oxide (NGO) nanosystem as a cancer-targeted nanocarrier of Pt complexes (Tf-NGO@Pt). This nanodelivery system exhibited good solubility under physiological conditions. Moreover, Tf-NGO@Pt showed higher anticancer efficacy against MCF human breast cancer cells than the free Pt complex, and effectively inhibited cancer-cell migration and invasion, with involvement of reactive oxygen species overproduction. In addition, nanolization also enhanced the penetration ability and inhibitory effect of the Pt complex toward MCF7 breast cancer-cell tumor spheroids. The enhancement of anticancer efficacy was positively correlated with increased cellular uptake and cellular drug retention. This study provides a new strategy to facilitate the future application of metal complexes in cancer therapy.

Cancer-targeted Selenium Nanoparticles Sensitize Cancer Cells to Continuous γ Radiation to Achieve Synergetic Chemo-Radiotherapy

Cancer radiotherapy with 125 I seeds demonstrates higher long-term efficacy and fewer side effects than traditional X-ray radiotherapy owing to its low-dose and continuous radiation but is still limited by radioresistance in clinical applications. Therefore, the design and synthesis of sensitizers that could enhance the sensitivity of cancer cells to 125 I seeds is of great importance for future radiotherapy. Selenium nanoparticles (SeNPs) have been found to exhibit high potential in cancer chemotherapy and as drug carriers. In this study, we found that, based on the Auger-electron effect and Compton effect of Se atoms, cancer-targeted SeNPs in combination with 125 I seeds achieve synergetic effects to inhibit cancer-cell growth and colony formation through the induction of cell apoptosis and cell cycle arrest. Detailed studies on the action mechanisms reveal that the combined treatments effectively activate intracellular reactive oxygen species (ROS) overproduction to regulate p53-mediated DNA damage apoptotic signaling pathways and mitogen-activated protein kinase (MAPK) phosphorylation and to prevent the self-repair of cancer cells simultaneously. Taken together, the combination of SeNPs with 125 I seeds could be further exploited as a safe and effective strategy for next-generation cancer chemo-radiotherapy in clinical applications.

Functionalized Selenium Nanosystem as Radiation Sensitizer of 125I Seeds for Precise Cancer Therapy

Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy.

Cancer-targeted design of bioresponsive prodrug with enhanced cellular uptake to achieve precise cancer therapy

Abstract Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of novel anticancer drugs to enhance the cancer targeting effects and biocompatibility, and decrease toxic side effects. Camptothecin (CPT) demonstrated strong anticancer activity in clinical trials but also notorious adverse effects. In this study, we presented a smart targeted delivery system (Biotin-ss-CPT) that consists of cancer-targeted moiety (biotin), a cleavable disulfide linker (S-S bond) and the active drug CPT. Biotin-ss-CPT was found to exhibit potent effects on the migration of cancer cells and induced apoptosis by induction of ROS-mediated mitochondrial dysfunction and perturbation of GSH/GPXs system, as well as activation of caspases. In vivo tumor suppression investigation including toxicity evaluation and pathology analysis, accompanied by MR images showed that Biotin-ss-CPT can be recognized specifically and selectively and taken up preferentially by cancers cells, followed by localization and accumulation effectively in tumor site, then released CPT by biological response to achieve high therapeutic effect and remarkably reduced the side effects that free CPT caused, such as liver damage, renal injury, and weight loss to realize precise cancer therapy. Taken together, our results suggest that biotinylation and bioresponsive functionalization of anticancer drugs could be a good way for the discovery of next-generation cancer therapeutics.

BSA-based Cu2Se nanoparticles with multistimuli-responsive drug vehicles for synergistic chemo-photothermal therapy

Functionalized-nanoparticles have been developed as novel therapeutic delivery platform for simultaneous drug loading and therapy over the past decade. Rationally-designed biocompatible nanosystem simultaneously with multistimuli-responsive property and synergistic therapeutic potential are highly desirable for modern biological applications. Herein, Cu2Se nanoparticles (Cu2SeNPs) with suitable size have been functionalized by bull serum albumin (BSA) through a simply, facile and controllable method. As a result, Cu2SeNPs modified by BSA (BSA-Cu2SeNPs) showed excellent biocompatibility and stability. The strong absorbance of BSA-Cu2SeNPs at near infrared region imparts them with high photothermal efficiency. Then loading doxorubicin (DOX, anticancer drug) on the surface of BSA-Cu2SeNPs, and consequently, a novel multifunctional nanosystem of BSA-Cu2SeNPs-DOX is designed. The BSA-Cu2SeNPs can achieve high DOX loading capacity (approximately 157 μg DOX per mg of Cu2Se). Furthermore, a rational and precise release of DOX from the BSA-Cu2SeNPs-DOX could be easily realized under the stimulates of the pH and temperature, which remarkably improved antitumor efficacy of combined chemotherapy and photothermal therapy triggered by 808 nm NIR laser. Thus, the BSA-Cu2SeNPs-DOX could serve as an ideal nanoplatform for cancer diagnosis and treatment in future. The results of cell experiments show that the BSA-Cu2SeNPs-DOX exhibited favorable selective cellular uptake cells. Under the NIR laser irradiation, BSA-Cu2SeNPs-DOX could induce the excessive expression of ROS, eventually leading to the death of U251 cells. Both in vitro and in vivo experiments indicate that the nanosystem of BSA-Cu2SeNPs-DOX showed excellent synergistic therapeutic effect and multistimuli-responsive drug vehicle, which will exert huge potential for future clinical application.