Nanomedicine approaches for sirolimus delivery: a review of pharmaceutical properties and preclinical studies

Figures & data

Figure 1. Schematic illustration of the mammalian target of rapamycin (mTOR) pathway and sirolimus (SIR) mechanism. mTOR integrates in/out from numerous upstream cues including several growth factors and interleukin-2 (IL-2). After entry into the cell, sirolimus associates with FK506 binding protein 12 (FKBP-12). The resulting complex interacts with the FKBP12-rapamycin binding domain located in the carboxyl terminus of mTOR and inhibits the mTOR kinase activity.

Figure 2. Indications for which sirolimus has been investigated. A growing number of evidence has demonstrated that sirolimus is beneficial for treating various diseases [13–27]. GVHD: Graft-versus-host disease; HIV: Human immunodeficiency virus; LAM: Lymphangioleiomyomatosis.

Figure 3. Schematic representation of various nanocarriers for sirolimus delivery which are currently under in vitro and preclinical evaluation.

Table 1. Nanocarrier compositions and characteristics of sirolimus liposomal formulations.

Nanocarrier composition	Size (nm)	Zeta potential (mv)	Entrapment efficiency (%)	Observations	Investigation status	Ref
DPPC, cholesterol, +/− DOPE	165–178	−41 to −40	73–77	Fusogenic pH-sensitive liposomes showed higher antiproliferative effects compared to conventional liposomes.	In vitro	[48]
DPPC, cholesterol, +/− PEG-poly (monomethylitaconate)- 6-(cholesteryloxycarbonyloxy) hexanol, +/− oleic acid	214– 240	−13 to −5	77–81	pH-sensitive liposomes improved selectivity and antiproliferative effect against cancer cell line.	In vitro	[49]
DPPC, cholesterol, DSPE-PEG and folate as targeting ligand	154	−13	88	Targeted theranostic thermal sensitive liposomes were suitable for tumour diagnostics as well as treatment.	In vitro/in vivo	[47]
PC, cholesterol	–	–	–	Liposomes improved graft survival, fibre outgrowth and neuroprotective effects.	In vitro/in vivo	[50]
SPC, cholesterol, +/− DSPE-PEG	155–181	−15–1	74–93	Antiproliferative activity against MCF-7.	In vitro	[51]
SPC, cholesterol, DSPE-PEG	124–137	−1–0	60–73	Co-loaded paclitaxel/sirolimus liposomes better controlled cancer growth.	In vitro/in vivo	[52]
EPC, cholesterol, DSPG, +/− DSPC	94–126	−8 to −5	73–98	Efficient inhibition of restenosis.	In vitro/in vivo	[44]
EPC, cholesterol, DSPG, DSPE-PEG	85–98	−11 to −8	99	Efficient inhibition of restenosis.	In vitro/in vivo	[53]
Phospholipids, cholesterol	150–500	–	–	Sirolimus liposomes were successfully prepared by rapid expansion of supercritical solution technology.	In vitro	[54]
PC, cholesterol, stearylamine/dicetylphosphate	100–165	Both positive and negative vesicles	–	Liposomes were not efficient for sirolimus solubilization.	In vitro	[55]
Lecithin, cholesterol	140–211	–	93–98	Liposomes increased tear production and were efficient for treatment of dry eye disease.	In vitro/in vivo	[56]

DOPE: dioleoylphosphatidylethanolamine; DPPC: dipalmitoylphosphatidylcholine; DSPC: distearoylphosphatidylcholine; DSPE-PEG: pegylated distearoylphosphatidylethanolamine; DSPG: distearoyl-sn-glycerophosphoglycerol; EPC: egg phosphatidylcholine; PC: phosphatidylcholine; SPC: soybean phosphatidylcholine.

Figure 4. Chitosan decorated sirolimus liposomes attenuated vascular restenosis following local delivery as confirmed by pathology, immunohistochemical and in vivo CT angiography. Reprinted from ref [46]. Copyright (2017), with permission from Elsevier.

Figure 5. Schematic structure of the theranostic targeted thermosensitive liposome (A) and its antitumour mechanism (B). Redrawn with permission from Pang et al. [47]. Copyright (2016) American Chemical Society.

Table 2. Nanocarrier compositions and characteristics of sirolimus polymeric nanoparticles.

Nanocarrier composition	Size (nm)	Zeta potential (mv)	Entrapmentefficiency (%)	Observations	Investigation status	Ref
PLGA	250	–	69	Periadventitial delivery of nanoparticles effectively reduced intimal hyperplasia.	In vitro/in vivo	[62]
PLGA	134–152	–	70<	Coencapsulation of sirolimus and a chemosensitizer (piperine) improved oral bioavailability of 4.8-folds.	In vitro/in vivo	[63]
PLGA, EGFR antibody as targeting ligand	274–287	−14 to −12	80 ± 4	Targeted nanoparticles showed superior antiproliferative activity over non-targeted nanoparticles and free drug.	In vitro	[64]
PLGA	180	–	88	Nanoparticles inhibited neointimal hyperplasia in vein graft without affecting the reendothelialization.	In vitro/in vivo	[65]
PLGA	307	–	80 ± 8	Nanoparticles enhanced sirolimus suppressive activity on dendritic cells and maintained an immunosuppressive profile in dendritic cells.	In vitro	[66,67]
PLA	233 ± 35	−30 to −20	–	Phagocytic activity of human polymorphonuclear neutrophils was promptly reduced but recovered. Therefore, they emerged as a robust cell species.	In vitro	[68]
Three nanoparticles: PLGA, PLA, Eudragit RS	180–280	–	–	Local delivery of sirolimus nanoparticles reduced neointimal growth. PLA formulation was the most efficient nanocarrier.	In vitro/in vivo	[69]
Chitosan/PLA	219–326	30	6–89	Sirolimus nanoparticles showed excellent immunosuppression in corneal transplantation.	In vitro/in vivo	[70]
Elastin-like polypeptides fused with FKBP12	4, 24	–	78, 99	Nanoparticles exerted potent therapeutic activity for Sjögren’s syndrome in a murine model.	In vitro/in vivo	[71]
Hyaluronic acid	10–11	−56 to −13	–	Hyaluronic acid nanoparticles improved pharmacokinetic profile of sirolimus and efficiently delivered drug to CD44-positive breast cancer cell.	In vitro/in vivo	[72]
N-isopropylacrylamide, methylmethacrylate, vinylpyrrolidone, acrylic acid	80 ± 34	−13 to −10	–	Oral delivery of nanoparticles robustly inhibited mammalian target of rapamycin pathway in a xenograft model of pancreatic cancer.	In vitro/in vivo	[73]
Poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)	170–180	∼0	84–100	High solubilization efficiency and sustained release profile were achieved by nanoparticles, proposed them as suitable carriers for immunosuppression in corneal transplantation.	In vitro	[74]
PEG200 end-capped poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)	207	–	92	Sustained delivery of sirolimus from nanocarriers enhanced cellular uptake and kinase inhibition efficiency.	In vitro	[75]
N-isopropylacrylamide, N-vinyl pyrrolidone, pegylated maleic polymer	54 ± 5	−8	84	Local delivery of nanoparticles to the injured artery inhibited intimal hyperplasia and promoted reendothelialization.	In vitro/in vivo	[76]

EGFR: epidermal growth factor receptor; FKBP12: FK506 binding protein; PEG: polyethylene glycol; PEG-PLA: polyethylene glycol-polylactic acid; PLA: polylactic acid; PLGA: poly lactic-co-glycolic acid.

Table 3. Nanocarrier compositions and characteristics of sirolimus micelles.

Nanocarrier composition	Size (nm)	Zeta potential (mv)	Entrapmentefficiency (%)	Observations	Investigation status	Ref
Methoxy poly(ethylene glycol)-poly(ε-caprolactone) block copolymer, +/− α-tocopherol	37, 101^a	–	90	Micelle formulations increased drug plasma concentration and decreased distribution into the brain.	In vitro/in vivo	[33]
Poly(ethylene glycol)-poly N-[N-(2-aminoethyl)-2-aminoethyl] aspartamide-b-poly(ε-caprolactone)	81–108	5–7	58–85	Sirolimus and siRNA micelles generated enhanced cytotoxicity and tumour regression in prostate cancer.	In vitro/in vivo	[83]
Poly(ethylene glycol)-block-poly(lactic acid)	37–44	–	–	Micelles containing paclitaxel, 17-AAG and sirolimus showed strong synergy in breast and lung cancer cells, potent synergistic anti-tumour activity in vivo and was well-tolerated after IV injection.	In vitro/in vivo	[80,81]
D-α-tocopheryl polyethylene glycol succinate	11	−4 ± 1	97 ± 1	Micelles significantly improved sirolimus oral absorption.	In vitro/in vivo	[84]
Methoxyl-poly(ethylene glycol)-succinic acid sirolimus conjugate	56, 94^b	−11	–	Combination of sirolimus and paclitaxel micelles improved potency against a multidrug resistant human breast cancer cell.	In vitro	[85]
Poly(ethylene glycol)-poly(propylene sulfide)	39 ± 1	–	41 ± 11	Sirolimus micelles prolonged skin allograft transplant survival.	In vitro/in vivo	[86]
Sulphated derivatives of Pluronic F-127 and poly(propylene sulfide)- poly(ethylene oxide) block copolymer	24	–	89 ± 10	Sulphate functionalized mixed micelles enhanced binding to collagen I coated surfaces, a potential for extracellular milieu binding.	In vitro	[87]
DSPE-PEG2000	14	−16 to −14	90–102	Phospholipid based micelles attenuated neointimal hyperplasia after balloon injury.	In vitro/in vivo	[53]
Amino-PEG–PE and N-palmitoyl homocysteine and cRGD as targeting ligand	10–15	–	–	Targeted micelles downregulated mouse cardiac endothelial cell as well as HUVEC production and inhibited release of pro-inflammatory cytokines.	In vitro	[88]
Cholesterol-polyethylene glycol	12–14	−1–0.4	77–82	Micelles showed a high scleral retention and permeation of sirolimus.	In vitro	[89]
O-octanoyl-chitosan-polyethylene glycol	41 ± 4	6.8 ± 0.3	86	Positively charged micelles showed a high scleral retention and permeation of sirolimus.	In vitro	[90]
Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate)	66–76	–	15–88	Micelles significantly reduced sirolimus toxicity, but showed similar biodistribution profiles as drug nanosuspensions.	In vitro/in vivo	[91]
Pegylated octadecyl lithocholate and LTTHYKL peptide as targeting ligand	122–130	−1–0	88–91	Targeted micelle was introduced as a potential carrier for colorectal neoplasia with significantly less systemic toxicity and comparable therapeutic efficacy to free drug.	In vitro/in vivo	[92]

^a α-Tocopherol incorporation increased the micelle size to 101 nm.

^b Paclitaxel incorporation increased the micelle size to 94 nm.

17-AAG: 17-allylamino-17-demethoxygeldanamycin; Amino-PEG–PE: 1,2-diacyl-sn-glycero-3-phosphoethanol-amine-N-[amino-poly(ethylene glycol)]; DSPE-PEG: pegylated distearoylphosphatidylethanolamine; IV: intravenous.

Table 4. Nanocarrier compositions and characteristics of sirolimus incorporated in miscellaneous nanoformulations.

Nanocarrier type	Nanocarrier composition	Size (nm)	Zeta potential(mv)	Entrapmentefficiency (%)	Observations	Investigation status	Ref
Magnetic nanoparticle	Glycerol monooleate coated Fe3O4, HER2 antibody as targeting ligand	130–275	∼30	∼95	Nanoparticles enhanced uptake and cytotoxicity in human breast carcinoma cell line.	In vitro	[99]
Magnetic nanoparticle	Fe3O4, mesoporous silica	∼80	−31	–	Dose-tunable co-delivery of hydrophobic and hydrophilic drugs (sirolimus–doxorubicin) improved tumour cell apoptosis and cytotoxicity.	In vitro	[100]
Perfuorocarbon nanoparticle emulsion	Perfuoro-15-crown-5 ether, phosphotidylcholine, phosphatidylethanolamine and glycerine	160–240	−15	–	Sirolimus nanoparticles improved skeletal muscle strength and cardiac contractile function efficiently targeting defective autophagy.	In vitro/in vivo	[101]
Solid self-microemulsifying drug delivery system	Capryol™ propylene glycol monocaprylate, glycofurol, TPGS, sucroester 15 and mannitol	108 ± 11	–	–	The formulation showed enhanced release rate, higher stability in acidic pH and improved oral bioavailability.	In vitro/in vivo	[102]
Nab-Rapamycin	Albumin protein	∼100	–	–	Adventitial injection of Nab-Rapamycin reduced restenosis in a porcine model by immunosuppressive and antiproliferative mechanism.	In vivo	[103]
Solid dispersion nanoparticle	PVP K30	∼250	–	–	Solid dispersion nanoparticles prepared by a supercritical antisolvent process enhanced sirolimus oral bioavailability.	In vitro/in vivo	[104]
Nanoparticle	PVP K90, SDS	∼30	–	–	The sirolimus nanoparticles prepared by a continuous flow method resulted in faster and improved oral absorption.	In vitro/in vivo	[105]
Niosome	Span 60, cholesterol, +/− PEG-poly (monomethylitaconate)- 6-(cholesteryloxycarbonyloxy) hexanol, +/− CHEMS	268–305	−16 to −11	63–71	pH-sensitive niosomes showed higher antiproliferative effects compared to conventional niosomes.	In vitro	[98]
Nanoemulsion	Traicetin, Tween 80, Tween 20, iso-propanol, PEG 400, propylene glycol, Labrasol, Cremophor RH 40	14–47	0–1	–	Oil-in-water Triacetin mediated nanoemulsions showed cytotoxicity against cancer cells and improved permeability across Caco2 cells.	In vitro	[106]
β-cyclodextrin based nanoparticle	Acetalated β-cyclodextrin	185–250	–	90<	Sustained release nanocarriers improved antiatherosclerotic activity of sirolimus.	In vitro/in vivo	[97]
Lipid-polyaniline nanoparticles	Emeraldine base polyaniline, DPPC, DSPE-PEG and folate as targeting ligand	141	−0.3	–	Imaging guided combinational photothermal and chemo cancer therapy.	In vitro/in vivo	[107]
SAINT-O-Somes	DSPE-PEG, SAINT-C-18, POPC, cholesterol and anti-human VCAM-1 as targeting ligand	128 ± 4	11 ± 1	73	Targeted SAINT-O-Somes efficiently inhibited AB8/13 cells migration and proposed as drug delivery vehicle to podocytes.	In vitro	[108]

CHEMS: cholesteryl hemisuccinate; DPPC: dipalmitoylphosphatidylcholine; DSPE-PEG: pegylated distearoylphosphatidylethanolamine; Nab: nanoparticle albumin-bound; PEG: polyethylene glycol; POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; PVP: polyvinylpyrrolidone; SAINT-C-18: 1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride; SDS: sodium dodecyl sulphate; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate; VCAM-1: vascular cell adhesion molecule-1.

Figure 6. Design of sustained sirolimus delivery nanomedicines based on acetalated β-CD (A), sirolimus concentrations in the blood and the aorta of C57BL/6 mice (n = 4, mean ± SEM), after subcutaneous administration of sirolimus nanoparticles at 3 mg/kg of drug (B). Therapy with sirolimus nanoparticle significantly reduced atherosclerosis in ApoE−/−mice (C). (C) Representative photographs of total aortas from each group and quantitative results subjected to various treatments. Reprinted with minor modification from Dou et al. [97]. Copyright (2016), with permission from Elsevier.

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