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

Abstract

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.

Blood circulation of soft nanomaterials is governed by dynamic remodeling of protein opsonins at nano-biointerface

“…Radiolabelling of SMPNs. Radiolabelling of SMPNs (SMPN-1, 3, and 9) was performed according to the following protocol 30 . Briefly, the dried SMPN-1 (11 mg, Mw-1.3 × 10 6 , 100 nmol) was dissolved in dry DMSO (5 mL) under argon and NaH (0.3 mg, 140 μmol) was added.…”

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

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“…Chemical moieties such as hydrazone, aconityl and acetal/ketal linkages are stable in blood circulation but undergo rapid hydrolysis at lower pH, potentially allowing payload release at infection sites [26,27,[46][47][48][49]. These are used heavily for the selective release of drugs in mildly acidic tumour environments [26].…”

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

“…In this way, conjugation of deferoxamine to 140 kDa polymer with Rh 10.6 nm prolonged blood-circulation time of deferoxamine 768-fold to half-life (t 1/2 ) 64 h in mice [96]. Conjugation of deferoxamine to hyperbranched polyglycerol increases blood-circulation time 484-fold to t 1/2 44 h [97].…”