A Multi‐Bioactive Nanomicelle‐Based “One Stone for Multiple Birds” Strategy for Precision Therapy of Abdominal Aortic Aneurysms

Abstract

AAAs are characterized by the abdominal aortic diameter ≥3 cm or having ≥50% increase in the largest diameter of the abdominal aorta. [3] The estimated prevalence of AAA is 4-8% among people over 65 years old. [3b,4] Most individuals with AAAs are asymptomatic, but rupture of AAA results in mortality as high as 90%. [3a,5] Therefore, AAA is a serious and lethal aortic disease. The natural process of AAA is implicated by the continuous enlargement of the infrarenal aorta, and the turbulent blood flow in the aortic lumen promotes the formation of intraluminal thrombus. [3,6] Once the aneurysm diameter is larger than 5.5 cm, the risk of AAA rupture remarkably increases. [3b] Thus far, surgical intervention, including open surgery and endovascular aneurysm repair (EVAR), remains the only available choice for effective management of AAA. [7] Nevertheless, the surgical intervention of AAA has shown various post-operative complications, such as infection, [8] endoleak, [9] cardiopulmonary events, [10] acute kidney injury [11] and spinal cord injury. [2,12] Moreover, ≈20-30% patients require re-intervention after surgery owing to reperfusion and associated secondary aneurysm rupture, leading to reduced patient compliance as well as increased surgical risk and mortality. [2,3] Besides, surgical treatment is not suitable for Abdominal aortic aneurysm (AAA) remains a lethal aortic disease in the elderly. Currently, no effective drugs can be clinically applied to prevent the development of AAA. Herein, a "one stone for multiple birds" strategy for AAA therapy is reported. As a proof of concept, three bioactive conjugates are designed and synthesized, which can assemble into nanomicelles. Cellularly, these nanomicelles significantly inhibit migration and activation of inflammatory cells as well as protect vascular smooth muscle cells (VSMCs) from induced oxidative stress, calcification and apoptosis, with the best effect for nanomicelles (TPTN) derived from a conjugate defined as TPT. After intravenous delivery, TPTN efficiently accumulates in the aneurysmal tissue of AAA rats, showing notable distribution in neutrophils, macrophages and VSMCs, all relevant to AAA pathogenesis. Whereas three examined nanomicelles effectively delay expansion of AAA in rats, TPTN most potently prevents AAA growth by simultaneously normalizing the pro-inflammatory microenvironment and regulating multiple pathological cells. TPTN is effective even at 0.2 mg kg −1 . Besides, TPTN can function as a bioactive nanoplatform for site-specifically delivering and triggerably releasing anti-aneurysmal drugs, affording synergistic therapeutic effects. Consequently, TPTN is a promising multi-bioactive nanotherapy and bioresponsive targeting delivery nanocarrier for effective therapy of AAA and other inflammatory vascular diseases.

Anti‐Inflammatory Nanotherapies Based on Bioactive Cyclodextrin Materials

“…[18][19][20][21] Chemically functionalizing specific molecular scaffolds is generally employed to synthesize bioactive materials. [22][23][24][25][26] Cyclodextrins (CDs) are oligosaccharides with a cyclic structure derived from starch. [27] The most commonly used CDs are α-, β-, and γ-CD, which contain 6, 7, and 8 glucose units, respectively.…”