Polymeric rapamycin nanoparticles encapsulating ponatinib cause regression of venous malformations in mice

Venous malformations (VMs) are caused by activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) and Abelson murine leukemia viral oncogene homolog 1 (c-ABL) pathways. Daily oral administration of rapamycin (RAPA), an mTOR pathway inhibitor, has limited effectiveness in promoting lesion regression in patients with TEK receptor tyrosine kinase (TIE2)-mutated VMs. This may be due to poor bioavailability, frequent dosing requirements, and off-target effects that make maintaining adherence difficult. Recent preclinical studies have shown that combination treatment with RAPA and a c-ABL inhibitor [ponatinib (PON)] resulted in regression of VMs in a murine model; however, daily oral dosing was required. Here, we describe the formulation of polymeric RAPA, which acts as both a polymeric drug and a drug delivery carrier. The polymer was synthesized by polymerization of methacryloylated RAPA and terminated with polyethylene glycol (PEG-pRAPA). PEG-pRAPA self-assembled to form 30-nanometer nanoparticles (PEG-pRAPA NPs) and enabled the encapsulation of PON (PEG-pRAPA@PON NPs). PEG-pRAPA@PON NPs provided sustained release of both PON and PEG-pRAPA in vitro, reducing AKT phosphorylation comparably to free RAPA and PON. In a murine model of VMs, a single intravenous dose of PEG-pRAPA@PON NPs caused 70% VM regression over 20 days and a 6.3-fold reduction in CD31-positive (human-derived) blood vessels. There was no evidence of systemic toxicity or organ dysfunction after treatment. These findings demonstrated that PEG-pRAPA is an effective polymeric drug and drug delivery platform and support the hypothesis that nanoparticle-based pharmacotherapy can be an effective treatment strategy for VMs.