Nanoparticles have increasingly been used for a variety of medical applications, most notably for the delivery of therapeutic and diagnostic agents. A large number of nanoparticle drug delivery systems have been developed for cancer treatment and various materials have been explored as drug delivery agents to improve the therapeutic efficacy and safety of anticancer drugs. Natural biomolecules such as proteins are an attractive alternative to synthetic polymers because of their safety. In general, protein nanoparticles offer a number of advantages including biocompatibility and biodegradability. Among available and promising protein materials, albumin is an attractive macromolecular carrier that has been shown to be biodegradable, nontoxic, metabolized in vivo to produce innocuous degradation products, non-immunogenic, easy to purify and soluble in water allowing ease of delivery by injection and thus an ideal candidate for nanoparticle preparation. The approval of albumin-bound paclitaxel (nab-paclitaxel, Abraxane, ABI-008) by FDA at 2005 for metastatic breast cancer not only exemplifies the clinical feasibility of this approach but also highlights that serum albumin is safe and clinical acceptable biomaterial for medical preparations. Currently, cancer therapy relying on a single therapeutic strategy remains suboptimal. The combination of two or more therapeutic approaches with different mechanisms can cooperatively prohibit cancer development and is a promising strategy for effective treatments of cancers with synergistic or combined effects. Meanwhile, considerable effort has been devoted to advanced therapeutics based on RNA interference, and a variety of siRNA-based therapeutics has been developed, showing great promise in disease treatments. Therefore, the combination of traditional chemotherapy with newly emerging siRNA-based therapy has gained more attentions. Recently, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Since that, it was thought that nanoparticles produced with albumins, including human serum albumin, might potentially be the choice for co-delivery of chemotherapeutic drugs and gene agents with high drug loading capacity and in combination with biodegradability, biocompatibility. Therefore, this three-year program project is proposed in attempt to characterize and optimize process parameters of high pressure homogenizers and ultrasonicators for production of albumin nanoparticle in the first year, to engineer the co-delivery of anticancer drug/siRNA into albumin nanoparticles in the second year, and to conduct in vivo pharmacokinetic and tumor inhibition efficacy study of co-delivery anticancer drug/siRNA albumin nanoparticle in the third year.
|Effective start/end date||8/1/16 → 7/31/17|
- Human serum albumin
- Anticancer drugs