Rational Design And Application Of Biomacromolecule-based Nanosystem In Cancer Theranostics

Nowadays, the rapid development of nanotechnology brings new horizons for cancer theranostics. Functional drug delivery nanosystem is built by effectively packaging therapeutic and imaging agents in one nanoscale nanocarrier to enhance cancer-targeted ability and attenuate systemic toxicities. Among inorganic and organic source of nanoparticles, biomacromolecule-based nanosystems have attracted great attention due to its excellent biocompatibility and biodegradability. The biosource of nanomaterials such proteins, peptides and nucleotides can be degraded and cleared out by systemic metabolism, thus avoiding long-term toxicity in the body. In this study, three kinds of nanocarriers including bovine serum albumin nanoparticles, phycocyanin nanoparticles and DNA origami were developed to realize the goal of drug trafficking in vivo, strengthened cancer-targeted ability, synergistic therapeutic outcomes of radiotherapy and chemotherapy and the overcoming of drug resistance. The main contents of this thesis were summarized as follows. In Chapter 1, the development of nanotechnology in cancer theranostics was summarized. What’s more, the catalogs and advantages of biomolecular nanomedicine were described, and the application in cancer theranostics was reviewed. To increase the therapeutic effect of radiotherapy, we fabricated a cancer-targeted nanosystem(FA-BSANP@Se) as novel radiosensitizer by using biocompatible bovine serum albumin nanoparticles(BSANPs) as carriers of organic selenocompound(PSeD) and using folate(FA) as the targeting ligand(Chapter 2). The combination of of PSeD and BSANPs drastically increases the ROS overproduction, which caused unprecedented scaleof DNA damage, thus triggering G2/M phase arrest and apoptosis. To eliminate the possibility of immunogenicity caused by BSANPs, we developed a non-immunogenic nanosystem, phycocyanin nanoparticles(PCNPs) as a novel protein nanocarrier for achieving safe and tumor-specific drug delivery in Chapter 3. This bio-responsive nanosystem(FA-PCNP@DOX) prolonged the half life of DOX in blood but rapidly released DOX in acidic lysosomal environment. FA-PCNP@DOX exhibited positive targeting accumulation in resistant cancer cells and overcame drug efflux by enhancing cellular uptake and retention time. Specifically, the overproduction of ROS caused mitochondrial damage and thus inhibited the transduction of ABC transporters. The inactivation of ABC transporters drastically increased the uptake and retention efficacy of DOX in RHepG2 cells, which triggered high level of apoptosis. Moreover, FA-PCNP@DOX efficiently accumulated in tumor and strengthened the anticancer effect of DOX by enhanced tumoral penetration. Importantly, FAPCNP@DOX eliminated hepatic, pulmonary, renal and cardiac toxicity caused by DOX. Furthermore, to improve the blood compatibility and anticancer ability of ruthenium complex(RuPOP) in cervical cancer treatment, cRGD-conjugated phycocyanin nanoparticles were fabricated as versatile nanoplatform of RuPOP(cRGD-PCNP@Ru). cRGD-PCNP@Ru improved the hemocompatibility of RuPOP by improving the hydrophily of RuPOP and inhibited the direct interaction between RuPOP and red blood cells. cRGD-PCNP@Ru exhibited selective cellular uptake against different cervical cancer cells through cRGD/integrin-mediated targeting. The strengthened accumulation of cRGD-PCNP@Ru enhanced the cytoxicities of RuPOP in Caski cells through the induction of ROS-mediated apoptosis. Importantly, cRGD-PCNP@Ru enhanced the accumulation of RuPOP in tumor spheroid and thus increased the inhibitory effect of tumor expansion. Besides, a cancer-targeted DNA origami as biocompatible nanocarrier of metal complexes was presented to achieve higher drug loading efficacy and advanced antitumor effect. The formation of unique tetrahedral nanostructure of DNA cages effectively enhanced the intercalation of ruthenium polypyridyl complexes(RuPOP), thus increasing the drug loading efficacy. Conjugation of biotin to the DNA-based nanosystem(Bio-cage@Ru) enhanced its specific cellular uptake, drug retention and cytotoxicity against a wide range of cancer cells. Different from free RuPOP and the cage itself, Bio-cage@Ru actively accumulated in cancer cells, and translocated to cell nucleus, where it underwent self-immolative cleavage in response to DNases, leading to triggered drug release and induction of ROS-mediated cell apoptosis. Moreover, in the nude mice model, the nanosystem specifically accumulates in tumor sites, thus exhibits satisfactory in vivo antitumor efficacy, and alleviates the damage of liver, kidney, lung and heart function of nude mice induced by RuPOP and tumor xenografts. In Chapter 5, the work in the whole thesis was fully summarized and the future studies were discussed. Collectively, our work demonstrates that the biodegradable nanosystems provide a safe and multifunctional platform to avoid cancer recurrence, unsatisfied therapeutic effects, severe side effects and drug resistance in clinical cancer therapy.