Design of Safe Nanotherapeutics for the Excretion of Excess Systemic Toxic Iron

Srinivas Abbina, Usama Abbasi, Arshdeep Gill, Kendrew Wong, Manu Thomas Kalathottukaren, Jayachandran N Kizhakkedathu
ACS Central Science 2019 May 22, 5 (5): 917-926
Chronic transfusion of red blood cells (RBCs) to patients with β-thalassemia, sickle cell disease, and other acquired anemic disorders generates significant amounts of bioactive iron deposits in the body. The inactivation and excretion of redox active iron(III) from the blood pool and organs are critical to prevent organ damage, and are the focus of iron chelation therapy (ICT) using low molecular weight Fe(III) specific chelators. However, the current ICT is suboptimal because of the short circulation time of chelators, toxicity, severe side effects, difficult regime of administration, and patient noncompliance. To address this issue, we have designed long circulating and biodegradable nanoconjugates with enhanced circulation time and well-defined biodegradability to improve iron excretion and avoid nonspecific organ accumulation. A series of iron chelating nanoconjugates were generated with deferoxamine (DFO) as the iron(III) specific chelator using polymer scaffolds containing structurally different acidic pH sensitive ketal groups. The type of degradation linkages used in the polymer scaffold significantly influenced the vascular residence time, biodistribution, and mode of excretion of chelators in mice. Remarkably, the conjugate, BGD-60 (140 kDa; R h , 10.6 nm; cyclic ketal), exhibited the long circulation half-life ( t 1/2β , 64 h), a 768-fold increase compared to DFO, and showed minimal polymer accumulation in major organs. The nanoconjugates were found to be nontoxic and excreted iron significantly better than DFO in iron overloaded mice. BGD-60 showed greater iron mobilization from plasma ( p = 0.0390), spleen ( p < 0.0001), and pancreas ( p < 0.0001) whereas BDD-200 (340 kDa; R h , 13.7 nm; linear ketal) mobilized iron significantly better from the spleen, liver, and pancreas ( p < 0.0001, p < 0.0001, and p < 0.0001, respectively) compared to DFO at equivalent doses. The nanoconjugate's favorable long blood circulation time, biodegradability, and iron excretion profiles highlight their potential for future clinical translation.


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