Smart Nanocarriers For On-demand Drug Delivery And Cancer Theranostics

Due to highly invasion and metastasis ability, malignant tumors(cancer) are extremely harmful to human life. Unfortunately, the antitumor chemo-drugs currently used for clinical tumor therapy are restricted by serious side effects, short therapeutic index and drug resistance. With the development of nanotechnology, smart nanocarriers that integrate multiple disciplines such as medical science, material science and biology, are emerging about new strategies to cure cancer. Because of its multifunction, multitarget and multimodality, smart nanocarriers have attracted tremendous attention with molecular imaging, drug delivery, diagnosing and tumor targeted therapy. Herein, indocyanine green(ICG)-loaded lipid-polymer nanoparticles, doxorubicin(DOX) and ICG co-loaded temperature-sensitive nanoparticles, and novel DOX-loaded oxygen nanocarrier were developed for cancer targeted imaging and precision phototherapy. We systematically studied the theranostic nanocarriers with the influence of nanoparticle size, on-demand drug release and oxidative stress-chemotherapy for combined phototherapy. Through smart drug delivery systems with highly-effective and visualized precision therapy, such new strategies were built to enhance the bioavailability and anticancer efficacy for cancer curing without relapse.1. Developing size-controllable lipid-polymer nanoparticles with photosensitizer ICG for cancer targeted photothermal therapyA key challenge to strengthen the anti-tumor efficacy of nanoparticles is to improve drug accumulation in tumor region through size control. Herein, indocyanine green(ICG) loaded poly(lactic-co-glycolic acid)(PLGA)-lecithin-polyethylene glycol(PEG) core-shell nanoparticles(INPs) with 3 different sizes(39 nm, 68 nm and 116 nm) were synthesized via single-step nanoprecipitation. These INPs showed excellent particle monodispersity, great size and fluorescence stability, and enhanced photothermal effect after NIR laser radiation compared with free ICG. Moreover, we demonstrated that 39 nm INPs can be most efficiently internalized into pancreatic carcinoma tumor cells(Bx PC-3) through cell uptake and subcellular localization in vitro, which further induced the best photothermal damage to Bx PC-3 cells compared with INPs with other sizes. The NIR fluorescence of ICG encapsulated in INPs were ideal probe for subcellular location and real-time in vivo metabolic distribution of INPs. However, 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in Bx PC-3 xenograft tumor model, revealing a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer NIR fluorescence imaging and photothermal therapy without adverse effect. The research have been published on Biomaterials(2014, 35, 6037-6046), and one patent has been applied(201310516245.5).2. DOX/ICG co-loaded temperature-sensitive liposomes(TSLs) with NIR-driven on-demand drug release for precision cancer therapySmart nanoparticles(NPs) that respond to external(such as light, ultrasound and hyperthermia) and internal stimulations(such as reduction/oxidation, and p H) have been developing to achieve optimal drug release in tumor. However, applying these smart NPs to attain high antitumor performance is hampered by limited drug carriers and inefficient spatiotemporal control. Here we report a noninvasive NIR-driven nanocarrier with DOX/ICG-coloaded temperature-sensitive liposomes(DI-TSL). In this theranostic system, thermo-responsive lipid is applied to controllably release drug, the fluorescence(FL) of DOX/ICG is utilized to real-time trace the distribution of NPs, and the drugs DOX and ICG are employed to treat cancer by chemo/photothermal therapy. The results demonstrate that DI-TSL exhibits uniform size distribution, excellent FL/size stability, and enhanced drug release through NIR laser irradiation. After endocytosis by MCF-7 breast adenocarcinoma cells, DI-TSL in cellular endosomes can cause hyperthermia through laser irradiation, then endosomes are disrupted and DI-TSL ‘opens’ to release DOX simultaneously for increased cytotoxicity. Furthermore, DI-TSL shows laser-controlled release of DOX in tumor, enhanced ICG and DOX retention by 7 times and 4 times compared with free drugs. Thermo-sensitive DI-TSL manifests high efficiency to promote cell apoptosis, and completely eradicate tumor without side-effect. The well-defined DI-TSL provides a nanoplatform to NIR-driven on demand drug release for combined cancer photo/chemotherapy. The research have been published on Scientific Reports(2015, 5, 14258), and one patent has also been applied(201410119236.7).3. Smart oxygen nanocarriers for boosted cancer therapy by ATP-responsive chemotherapy and amplified ROS cytotoxicitySmart hybrid nanocomposite(A/D-ONC) is developed with polymeric core entrapping hemoglobin and cationic shell absorbing doxorubicin(DOX)-intercalated DNA duplex. Oxygenated A/D-ONC donates abundant O2 to mitochondria, which dramatically up-regulates intracellular ATP amount to promote the release of DOX from ATP-responsive A/D-ONC and successfully converts growth-beneficial ATP to the activator of detrimental chemotherapy, and apparently increases reactive oxygen species(ROS) content to amplify the cytotoxicity. Combining with both effects, A/D-ONC realizes 438% increase of lethality for half-maximal cancer cell inhibition compared with that of only DOX. The oxygen nanocarrier opens up a new therapeutic window for cancer therapy by O2 interference. The research has been accepted by Advanced Healthcare Materials(DOI: 10.1002/adhm.201600121).