Multifunctional Nanoparticles for Anticancer Gene Delivery and Tumor Monitoring

Abstract

Cancer is a genetic disease originating from the accumulation of gene mutations in a cellular subpopulation. Although many therapeutic approaches have been developed to treat cancer, recent studies have revealed an irrefutable challenge that tumors evolve defenses and escaping mechanisms against some therapies. Gene therapy may be the ultimate panacea for cancer by correcting the fundamental genetic errors in tumors. However, nucleic acids cannot serve as stand-alone therapeutic agents as they need carriers for protection during transportation to prevent degradation. Since nucleic acids are large in size and highly anionic, they are generally repelled by cell membranes and hence denied of cytoplasmic entry. Gene carriers also serve to ferry nucleic acids across biological barriers. Moreover, nucleic acids need to be precisely delivered to target cancer cells to initiate effective therapeutic genetic modifications. In addition to achieve theloading, protection and transportation of nucleic acids, gene carriers need to remain stable and biocompatible to be suitable for clinical applications. These demanding criteria necessitates a robust and multifunctional system for gene delivery. From the advent of nanotechnology in the 1980s, marked by the invention of scanning tunneling microscopy, human knowledge in atom manipulation and nanomaterials synthesis has been advancing rapidly.1 Nanomaterials have interfaced with the biomedical field mainly as therapeutic carriers. Nanomaterials can be tailored in size, shape and elemental composition to meet the demands of therapeutic loading capacity, biocompatibility, prolonged circulation time and cellular uptake. Robust nanocarriers provide therapeutic payloads such as chemically unstable drugs, nucleic acids and peptides with protection against hydrolysis and enzymatic degradation. In addition, unique physical properties of certain nanomaterials offer more versatility in therapy modalities. Inorganic nanomaterials are well-positioned to serve as nanocarriers for combinatorial therapeutics delivery. Such nanocarriers typically consist of an inorganic core and a polymeric surface coating. The physicochemical properties of inorganic cores, including elemental composition, size and shape, may be precisely controlled during synthesis and in turn achieve tunable theranostic (therapeutic and diagnostic) properties. Polymeric coatings and ligands can be conjugated onto the rigid inorganic cores to confer desired biocompatibility, nucleic-acid/drug-loading capacity, tissue-targeting capability to inorganic nanocarriers. With inorganic cores serving as a rigid support for polymeric coatings, combinations of nucleic acids and other types of antitumor drugs can be loaded and delivered without significantly altering the size or shapes of the nanocarriers. Furthermore, inorganic nanomaterials also enable additional treatment modalities such as hyperthermal ablation and radiotherapy enhancement due to their unique magnetic and photo-electric properties. The engineering of nanoscale inorganic carriers of cancer therapeutics has shown promising results in efficacious and safe delivery of nucleic acids to treat oncological diseases in small-animal models. When these nanocarriers are used for co-delivery of gene therapeutics along with auxiliary treatments, the synergistic combination of therapies often leads to an amplified health benefit. Integrating multiple functionalities in a single nanosized construct requires sophisticated molecular design and precise execution of assembling procedures. Current multifunctional theranostic nanoparticle designs often suffer from one or multiple of the following shortcomings including poor biocompatibility, limited payload capacity, structural instability in physiological environment and insufficient bioavailability at tumor sites. This dissertation aims to address these issues by exploring novel designs of nanoparticles which can simultaneously serve as effective gene delivery carriers and imaging agents. Multiple nanoparticle designs were explored for gene delivery and imaging applications. Specifically, iron oxide-based nanoparticles for imaging apoptotic tumor cells in vivo and delivering plasmid DNA to cancer cells in vitro were developed and showed promising results. A novel polymeric coating was also developed for effective mRNA delivery. This polymeric coating has the potential to be installed onto the iron-oxide nanoparticle delivery platform equip it with mRNA delivery capability.