Inhibition of tumor angiogenesis and growth by nanoparticle-mediated p53 gene therapy in mice

Abstract

Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53NPs. We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs. controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this is accomplished is disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting

“…We used PTX as a model anticancer agent because of its effectiveness against lung cancer (41,42). Polymeric nanoparticles formulated with a biodegradable and biocompatible polymer, poly(DL-lactide-co-glycolide) (PLGA), was used to load PTX in MSCs (43). Previous studies have shown that following endocytic uptake into cells, PLGA nanoparticles escape the endo-lysosomes and are retained in the cytoplasm for several days (44).…”

Nano-engineered mesenchymal stem cells as targeted therapeutic carriers

“…Drug-loaded nanoparticles are readily formulated with the FDA-approved, biodegradable and biocompatible polymer, poly (DL-lactide-co-glycolide) (PLGA) [11]. Previous studies have shown that PLGA nanoparticles are internalized into cells through endocytosis and a fraction of the internalized particles escape the endolysosomal pathway to reach the cytoplasm [12].…”

Tailoring of physicochemical properties of nanocarriers for effective anti‐cancer applications

“…The interplay of aggregates (strong bonding between nanoparticles) and agglomerates (loose bonding between the nanoparticles) with biological media has not been fully understood and hence not explored as an optimizing parameter for nanocarriers in anti‐cancer studies. Agglomerates/aggregates primarily occur when there is the larger influence of Van der Waal forces, as compare to the electrostatic repulsive forces . The agglomerated or the aggregated nanoparticles behave differently inside the biological system compared with suspended nanoparticles (i.e.…”