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Restenosis remains the main reason for treatment failure of arterial disease. Sirolimus (SIR) as a potent anti-proliferative agent is believed to prevent the phenomenon. The application of exosomes provides an extended-release delivery platform for SIR intramural administration. Herein, SIR was loaded into fibroblast-derived exosomes isolated by ultracentrifugation. Different parameters affecting drug loading were optimized, and exosome samples were characterized regarding physicochemical, pharmaceutical, and biological properties. Cytotoxicity, scratch wound assays, and quantitative real-time PCR for inflammation- and migration-associated genes were performed. Restenosis was induced by carotid injury in a rat carotid model and then exosomes were locally administered. After 14 days, animals were investigated by computed tomography (CT) angiography, morphometric, and immunohistochemical analyses. Western blotting confirmed the presence of specific protein markers in exosomes. Characterization of empty and SIR-loaded exosomes verified round and nanoscale structure of vesicles. Among prepared formulations, desired entrapment efficiency (EE) of 76% was achieved by protein:drug proportion of 2:1 and simple incubation for 30 min at 37 °C. Also, the optimal formulation released about 30% of the drug content during the first 24 h, followed by a prolonged release for several days. In vitro studies revealed the uptake and functional efficacy of the optimized formulation. In vivo studies revealed that %restenosis was in the following order: saline > empty exosomes > SIR-loaded exosomes. Furthermore, Ki67, alpha smooth muscle actin (α-SMA), and matrix metalloproteinase (MMP) markers were less expressed in the SIR-exosomes-treated arteries. These findings confirmed that exosomal SIR could be a hopeful strategy for the prevention of restenosis., (© 2023. Controlled Release Society.)

Sirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor with immunosuppressive, antiproliferative, antiangiogenic, antifungal, anti-restenosis and anti-inflammatory properties. However, its clinical application is often hampered by poor aqueous solubility, first-pass metabolism, transport by p-glycoprotein efflux pump, limited oral bioavailability and nonspecific distribution in off-target sites. Recently, various formulation strategies have emerged to overcome these limitations. Among these, pharmaceutical nanotechnology with numerous advantages has great potential for sirolimus delivery. Up to now, the only nanoparticle based FDA approved formulation in the market is Rapamune ® tablet which is composed of drug nanocrystals. This review focuses on recent studies that have been investigated various nanostructured carriers such as liposomes, micelles, polymeric nanoparticles, nanocrystals, magnetic nanoparticles, albumin nanoparticles, solid dispersion nanoparticles and niosomes for sirolimus delivery (in organ transplantation, cancer, vascular restenosis, etc.).

Assuring the efficient local delivery via biocompatible nanosystems can be considered as a promising therapy for restenosis. The aim of the present study was preparation, in vitro characterization, and in vivo efficacy evaluation of sirolimus containing chitosan decorated liposomes for restenosis treatment. Liposomes were coated with chitosan, leading to ∼38nm increase in the particle size and a positive shift in the zeta potential from -1mV to +21mV. Chitosan modification was also confirmed by TEM, increased stability against detergent solubilization, and FTIR analyses. High entrapment efficiency (≥83%) and sustained release behaviors were demonstrated in both coated and uncoated vesicles. Compared to control groups, treatment of balloon injured rats with uncoated and chitosan-coated liposomes (50μg sirolimus) significantly reduced stenosis by 39% and 62%, respectively. The effect was also confirmed by immunohistochemical and in vivo CT angiography imaging studies. Chitosan-coated liposomes could be a novel platform for restenosis treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: To develop an ameliorated sirolimus (SIR) liposome for intramural delivery, the effects of various carrier physicochemical parameters on the antirestenosis efficacy were evaluated., Materials & Methods: Different liposomes were prepared, characterized and administered to balloon injured rats (12 animal groups). Their efficacies were investigated using morphometric, immunohistochemical and in vivo computed tomography imaging analyses., Results: The antirestenosis efficacy of SIR liposomes decreased in the following order: cationic 100 nm vesicles ≥ cationic 60 nm vesicles > neutral 100 nm vesicles ≥ stealth 100 nm vesicles > anionic 100 nm vesicles. The 100 µg SIR loaded in cationic liposomes showed almost no artery stenosis., Conclusion: Appropriate modulation of physicochemical characteristics makes it possible to optimize the liposomes for local delivery.

Restenosis after angioplasty remains a serious complication in clinical cardiology. This study aims to investigate the stealth colloidal systems for local intra-arterial drug delivery. Micelles from polyethylene glycol conjugated with phosphatidylethanolamine and PEGylated liposomes loaded with sirolimus were prepared and characterized with regard to their loading efficiency, particle size distribution, zeta potential, morphology, nuclear magnetic resonance spectroscopy, drug release profile and stability. The antirestenotic effects of the sirolimus-loaded micelles (14 nm) and liposomes (90 nm) were evaluated and compared in the rat carotid injury model following local intravascular delivery. In comparison to control groups, treatment of balloon injured rats with drug loaded micelles and nanoliposomes significantly reduced vascular stenosis by 42% and 19%, respectively (P<0.05). In addition, the luminal area was significantly enlarged by 39% and 60% following treatment with sirolimus-loaded liposomes and micelles, respectively (P<0.05). Immunohistochemistry revealed that sirolimus-loaded nanocarriers suppressed cell proliferation (Ki67-positive cells) as compared to control groups without affecting the density of smooth muscle actin staining. These results suggest that both colloidal nanocarriers could serve as effective intramural drug delivery systems for the treatment of restenosis; however, phospholipid based micelles provided better antirestenotic effects than PEGylated liposomes., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The main objective of this study was to formulate an effective controlled-release liposomal drug delivery system for sirolimus (SIR), a potent antiproliferative and anti-inflammatory drug, to be used for the treatment of restenosis following local vascular delivery. Liposomes were prepared using remote film loading method and characterized with regard to entrapment efficiency (EE), size distribution and zeta potential. The effects of key formulation and proceeding variables on both EE and drug release were studied using a fractional factorial design. By means of this entrapment technique, 98% SIR incorporation was achieved. Nanoliposomes were found to have average size of 110 nm and zeta potential of -9 mV. Developed formulations were found to have prolonged drug release for up to 3 weeks in vitro; this was best fitted by the Higuchi model. Other scopes of this work were to determine the applicability of sirolimus-loaded nanoliposomes (SIR-L) as drug carriers for the treatment of restenosis and to evaluate the effect of the presence of rigid lipids on the in vivo efficacy of the liposomal carrier of SIR. In vivo studies in balloon injured rat carotid arteries revealed the potential of SIR-loaded liposomes as efficient local and controlled drug delivery systems to reduce restenosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Breast cancer accounts for significant mortality worldwide. Here, we develop a localized, sustained-release delivery system for breast cancer therapy. Sirolimus (SIR) core-shell nanofibers (NFs) are fabricated by coaxial electrospinning with poly(ε-caprolactone) (PCL) for the core and chitosan and PCL for the shell. The NFs were characterized by SEM, AFM, TEM, XRD, FTIR, water uptake, water contact angle, mechanical properties, drug content, and in vitro release. In vitro and in vivo anticancer effects were investigated. A sustained release behavior is observed during 480 h that is more extended compared to monoaxial NFs. In vitro cytotoxicity and Annexin V/propidium iodide assays indicate that SIR-loaded coaxial NFs are effective in inhibiting proliferation of 4T1 and MCF-7 cells. Implantation of SIR NFs in 4T1 breast tumor-bearing mice inhibits tumor growth significantly compared to free drug. Histopathological examination shows that suppression of tumor growth by SIR NFs is associated with apoptotic cell death. Furthermore, anti-cancer effects are also confirmed by decreased expression levels of Ki-67, MMP-2, and MMP-9. Histological observation of organs, serological analyses, and the lack of body weight changes indicate in vivo safety of SIR NFs. Altogether, we show here that incorporation of SIR into core-shell NFs could act as an effective drug release depot and induce a sustained antitumor response. [ABSTRACT FROM AUTHOR]