A New Drug And Delivery Platform As An Alternative To Stent Placement Surgery
Cardiovascular disease remains the number one reason for mortality and morbidity in the US, particularly given the ever-increasing prevalence of metabolic syndromes like diabetes and obesity. When a vasculature is occluded or stenotic, insufficient blood supply will lead to ischemia, followed by grave consequences like a heart attack or stroke. To restore the patency of the clogged vasculature, vascular surgeons and cardiologists have long been resorting to surgical intervention strategies such as open bypass surgeries and endovascular procedures.
In recent decades, we are witnessing a shift toward endovascular procedures as the preferred strategies, due to the many obvious advantages, ranging from minimal risk to a much shorter length of hospital stay. Indeed, angioplasty and stent placement surgery, currently one of the most welcomed and widely-practiced endovascular procedures, have demonstrated consistent and effective outcomes in immediately restoring vessel patency and alleviating symptoms. However, endovascular interventions inevitably cause vascular damage, and, in many cases, lead to a re-narrowing of the vessel, or restenosis.
Indeed, in the bare metal stent era, the incidence rate of restenosis can reach as high as 40% based on reports from various clinical studies. And despite the advances in anti-restenosis therapies, for example, the deployment of drug-eluting balloons and stents, there is still at least 10% overall patients that regardless develop this recurring disease. What’s worse is that the cut in the restenosis risk comes at a huge cost: while drug-eluting stents kill smooth muscle cell overgrowth and restenosis, they also intoxicate the fragile endothelium that supposedly should serve as the “barrier” and “guards” of the vessel lumen; and because of the collateral damage on endothelium, clinicians are observing an increase in risk of late and very late thrombosis, a grave complication whose onset is not only difficult to predict, but one that is also very deadly.
It is now clear that not only the drug coated on the stent, but also the stent itself, play a huge contribution to unwanted thrombosis risk here. On the one hand, drugs like sirolimus, paclitaxel, and their myriad respective derivatives (e.g. everolimus, tacrolimus), are the go-to choices to be coated on drug-eluting stents; both experimental and clinical evidence clearly show that their non-discriminative toxicity is amongst the major culprits for stent thrombosis. On the other hand, there is an ever-increasing awareness that the presence of a solid metal stent constitutes a chronic and continuous stimulation to the vessel wall as well as a risk for disturbed hemodynamics, both of which are closely linked to thrombogenicity. In this regard, concerted efforts are needed from both vascular drug discovery experts and biomaterial engineering teams, in order to address the negative complications presented by drug-eluting stents.
Toward this goal, a multidisciplinary research team was formed between UW-Madison and OSU. Dr. K Craig Kent, currently dean of the Ohio State Wexner Medical Center, is a seasoned vascular surgeon and physician-scientist in translational researches, who initiated the first high throughput drug screening campaign to find better replacement for sirolimus and paclitaxel. This early collaboration with Dr. Lian-Wang Guo, a molecular vascular biologist and pharmacologist, led to the first milestone of this long-term project, which is the identification of multiple potent yet endothelium-friendly anti-restenotic agents (e.g. JQ1) and intervention targets (e.g. BET epigenetic reader protein, ER stress PERK kinase) that could potentially outperform the status quo drug.
With better drugs in hand, the two vascular experts teamed up with Dr. Shaoqing Sarah Gong, a distinguished bioengineer from UW-Madison, to march toward the next phase: finding a better alternative delivery platform that can skip the need of the permanent presence of a stent. However, this is not an easy goal, and many previous endeavors have ended up in failure. Abbott developed a bioresorbable stent product, ABSORB, aiming to replace metallic stents; unfortunately, the ABSORB III trial result published in last year’s New England Journal of Medicine dealt a major blow to the industry, highlighting the need for alternative stent-free strategies to approach this topic.
Nanomedicine and nanoplatforms are amongst the most competitive options and have shown great potential in achieving such stent-free, targeted delivery. Research groups across the globe have identified numerous designs of nanoplatforms, mostly based on man-made materials, that can deliver therapeutics specifically to vascular injury sites with high efficiency. One such interesting design is from Dr. Melina Kibbe’s group, who reported a supramolecular nanofiber that is harnessed with targeted delivery capacity by simply manipulating its shape.
The joint group of Drs. Kent, Guo, and Gong, on the other hand, took a different route toward their nano-design, which is by taking notes directly from mother nature herself. More specifically, as described in their article in the September issue of Biomaterials, they “camouflaged” their ultrasmall nanoparticles with vesicles of platelets, the very cell types that serve as the “first-responders” whenever there’s injury in the human body. By coating platelet membrane around a cluster of ~200-500 nanoparticles, the joint research team successfully manufactured a bio-inspired “cluster bomb,” which not only has a very high drug-loading capacity but also can provide targeted delivery to injured vasculature, just like what platelets would do in the circulatory system. And by loading this bio-inspired nanoplatform with their previously tested drug, JQ1, the authors successfully achieved outstanding inhibition on restenosis in a rat angioplasty model, all while using as little as 1/70 of the previously estimated dosage should it be delivered systemically.
Moreover, this combination of new drug and new delivery platform showed superior performance compared to the status quo, sirolimus, in both anti-restenotic effects as well as endothelium protection. As a bonus, the injectable stent-free therapy can enable a much more flexible regimen for patients, for example, ad lib based on the discretion of the attending physicians; whereas the conventional stent-based therapy can only allow a fixed drug-release and therapeutic window after the permanent deployment of metallic stents.
The Kent/Guo/Gong lab is still working on testing other membrane options, such as leukocyte membranes, for treating vascular diseases. However, there’s something special about choosing platelet-mimicking nanoclusters as the prototype design. With their end goal being pushing the products into the clinic, there are several major issues that need to be addressed: one is mass-producibility and the other is immunocompatibility. For the former, there is a pleural and accessible supply of platelets from blood, either from autologous or allogeneic sources.
The fact that platelet is anucleate also makes mass-producibility more likely, because there are much less intracellular organelles that need to be cleared out during the membrane isolation process, hence leading to less complicated membrane manufacturing process in comparison to nucleate cells. And regarding the immunocompatibility concern, platelets endogenously express CD47, a surface marker that can help evade immune clearance.
Indeed, ABO non-matched platelet transfusion is a common practice in the blood transfusion unit, and there are typically no severe systemic reactions within the first several transfusions. Under certain scenarios when only strictly autologous platelets are allowed and patients’ own whole blood cannot meet the needs, patient-specific iPSC-derived platelets can be an alternative source, or, as a compromise, HLA-matched platelets from blood bank can also be considered.
These findings are described in the article entitled A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters, recently published in the journal Biomaterials.
This work was conducted by Bowen Wang, Urabe Go, Lian-Wang Guo, and K Craig Kent from the Ohio State University, and Guojun Chen, Ruosen Xie, Yuyuan Wang, Xudong Shi, and Shaoqing “Sarah” Gong from the University of Wisconsin-Madison. The drug-screening experiments were supported by an American Heart Association (AHA) Grant-in-Aid award to Drs. K Craig Kent and Lian-Wang Guo (14GRNT20380854) and an AHA pre-doctoral fellowship to Dr. Bowen Wang (16PRE30160010), and the bio-inspired nanoplatform experiments were supported by a National Heart, Lung and Blood Institute (NHLBI) R01 research grant to Drs. K Craig Kent, Lian-Wang Guo, and Shaoqing “Sarah” Gong (R01HL143469-01). Additional funding from NIHK25CA166178 (to S.G.) and R01HL133665 (to L.W.G.)