Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors.

Advances in molecular imaging modalities have accelerated the diagnosis and treatment of human diseases. However, tumors less than 1 cm in size still remain difficult to localize by conventional means because of the difficulty in specific targeting/delivery to the tumor site. Furthermore, high nonspecific uptake in the major organs and persistent background retention results in low tumor-to-background ratio. The targeting and therapy of gastrointestinal stromal tumors (GIST) using nonsticky and renal clearable theranostic nanoparticles (a.k.a. H-Dots) are demonstrated. H-Dots not only target GIST for image-guided surgery, but also tailor the fate of anticancer drugs such as imatinib (IM) to the tumor site resulting in efficient treatment of unresectable GIST. In addition, H-Dots can monitor targetability, pharmacokinetics, and drug delivery, while also showing therapeutic efficacy in GIST-bearing xenograft mice following surgical resection. More importantly, IM loaded H-Dots exhibit lower uptake into the immune system, improved tumor selectivity, and increased tumor suppression compared to free IM, which accumulates in the spleen/liver. Precisely designed H-Dots can be used as a promising theranostic nanoplatform that can potentially reduce the side effects of conventional chemotherapies.

Renal clearable nanochelators for iron overload therapy.

Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO's own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.

Chemical Modulation of Bioengineered Exosomes for Tissue-Specific Biodistribution.

The physicochemical properties of nanomaterials play a key role in tissue-specific targeting by reducing nonspecific background uptake as well as controlling biodistribution and clearance. Due to the strong influence of surface chemistry, chemical modulation of bioinert exosomes with chargeable and traceable small molecule fluorophores has a significant effect on the targeting, stability, and toxicity of the final conjugates. In this study, charge-variable exosomes are designed by conjugating their surface proteins with near-infrared fluorophores to control the in vivo fate of exosomes. Interestingly, zwitterionic fluorophore-labeled exosomes show rapid renal clearance with minimum to none nonspecific tissue uptake, whereas anionic exosomes are excreted through the hepatobiliary route with high uptake in the liver. The biodistribution and pharmacokinetics of exosome conjugates are comparable to their corresponding free fluorophores, demonstrating that the surface characteristics govern the fate of final conjugates in the living organism. Such unique surface properties of chemically modulated exosomes are confirmed in the lymphatic system after intradermal administration, which results in distinctive kinetic profiles in the secondary lymphoid tissues. This finding can subsequently serve as the foundation for developing tissue-specific exosome-based therapeutics.