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. 2022 Sep 14;14(9):1940. doi: 10.3390/pharmaceutics14091940

Table 3.

Summary of microfluidic manufactured lipid-based nanomedicines.

Delivery System/Lipids Drug/API Chip
Design		 FRR
(aq:org)		 TFR
(mL·min−1)		 In Vitro Findings In Vivo Findings Optimized Formula Ref.
Mean Diameter (nm) PDI LE%
Lipoplex/
DOTAP:EPC:DOPE		 pDNA FF 10:1 140 mm·s−1 Transfection efficacy ~10 × 107 relative light units (RLU)·mg of protein−1 NA ~135 ~2.3 NA [270]
Patterned walls FF Transfection efficacy ~6 × 107 RLU·mg of protein−1 ~115 ~2.0
Lipid nanoparticles/
mPEG-DSPC:POPC 		AmB NASHM 3:1 12 IC50: 0.085 μg·mL−1, hemolytic at ≥25 μg·mL−1 NA ~39 ~0.115 88 [271]
T-junction 24
Liposomes/
SPC:Chol (3:1 w/w)		 CBD T-junction and zig zag or split and combine 1:5 10 NA NA ~110 ~0.13 ~73 [236]
Lipoplex/
DOTAP:DOPE:DOPC:DSPE-PEG2000-FolA or
DOTAP:DOPE:DOPC:DSPE-PEG2000 		siRNA HFF 9:1 0.0167 In vitro studies on wildtype epithelial carcinoma KB cells show endosomal uptake in the perinuclear region NA ~40 NA ~60 [242]
Targeted Lipoplex/
DODMA:DOTMA or DCChol:EggPC:mPEG-DSPE) modified with Tf		 siRNAs
(LOR-1284)		 HFF 5:1 0.025−2.000 siRNA complex was stable in serum for 8 h compared to 40% of free siRNA; no significant cytotoxicity in MV4-11 cells; 6.14-fold reduction in IC50 for siRNA complex (105.27 nM) and increased downregulation compared to free siRNA 20% of IV dose remained in plasma after 24 h (t1/2: 10.2 h, AUC: 5.5 h μg·mL−1) compared to 1% for free siRNA. (t1/2: 2.93 h); 3-fold increase in t1/2 and decreased protein expression by 86%. ~80 NA 91.5 ± 4.5 [272]
Transferrin-conjugated Lipoplex (Tf-LNPs-MF)/
DOTMA:DODMA:EPC:Chol:mPEG-Cho 		siRNAs SHM 3 inlets: 3:1:1 NA Increased permeability in HepG-2 cells by Tf receptor mediated uptake Tf-LNPs-MF-siRNA in blood was >100 ng·mL−1 and t1/2 was 25.6 h 48 h post IV vs. <10 ng·mL−1 and t1/2 of 15.1 h for free siRNA 132.6 0.129 N/A [224]
Lipoplex/
DLinKC2-DMA(cationic lipid):Chol:DSPC:PEG2000-C-DMA		 siRNAs SHM 3:1 0.02−4.00 NA 50% silencing in hepatocytes at 10 µg·kg−1 in mice 28−54 <0.1 ~100 [228]
Lipoplex/
DSPC:mPEG2000-DMG:Chol:range of cationic lipids 		siRNAs SHM 1:1:2 (lipids: siRNA: buffer 1.2 NA Gene silencing potency of >90% at 1.0 mg·kg−1 in mice 90.5 NA ∼80 [258]
Cubosomes/
DOTAP:Glycerol monooleate (GMO):GMO-PEG2000 		siRNAs SHM 6:1 4 Gene-knockdown efficiency of 73.6% for a ρ = nDOTAP/nNA of 3 vs. Lipofectamine (45.8%) efficiency; Up to ρ = 10, no significant damage to cell membranes. NA 77 0.06 >90% [273]
Lipid nanoparticles/
YSK05 (cationic pH-sensitive lipid):Chol:mPEG2000-DMG 		siRNA SHM 3:1 1.5 Particles with 1%, 1.25%, and 1.5% w/w and <2% mPEG (67.1, 57.3, and 53.8 nm) show high and similar gene silencing efficiencies FVII gene silencing activity of 50% Chol-rich 1% mPEG-LNPs was higher than 3% mPEG-LNPs 32−67 NA ∼100 [274]
Lipid nanoparticles/
YSK05 (cationic pH-sensitive lipid):Chol:mPEG2000-DMG		 siRNA Baffle mixers 3:1 0.5 NA YSK-LNPs showed high FVII gene-silencing activity with no dose dependency 80 0.1 >90% [269]
Liposomes/
EPC:DMPC:DPPC:DSPC		 Metformin (M) and glipizide (G) NASHM 5:1 5–15 Sustained release was achieved NA 80–90 0.11–0.22 ~20 (M) ~40 (G) [250]
Lipid nanoparticles/
DSPC:D-Lin-MC3-DMA:Chol:PEG-DMG		 siRNA NASHM 3:1 12 79% mRNA knockdown produced by 1 μg siRNA 15 mg·kg−1 (3 doses IV over 24 h) results in a 100% uptake in peripheral blood cells that remain positive until day 10; no liver toxicity or other biochemical alternation; after 10 IV doses over 35 days, luciferase signal decreased 0.75-fold, while it increased in control mice 1.6-fold; 60% knockdown efficiency of BCR-ABL by LNP-anti-BCR-ABL siRNA in sorted leukemia cells from the myelosarcoma mouse tissue 55.03 0.046 >90 [275]
Liposomes/
DSPC:mPEG2000-DSPE 		Dox, ICU SHM 10:1 and/or 16:1 5 After 48 h, ~90% of drug was released (first order); less cytotoxic to MCF-7, MDA-MB 231 and BT-474 breast cancer cells vs. free doxorubicin NA ~100 0.2 >80 [276]
Liposomes/
DMPC:DPPC:DSPC		 Curcumin NASHM 5:1 17 Increased 700-fold the aqueous curcumin solubility When co-administered with cisplatin, it enhances cisplatin’s efficacy in multiple mouse tumor models with decreased nephrotoxicity ~125 <0.2 87.7 [277]
Nanoemulsions/
Cold-pressed hempseed oil:lecithin:Poloxamer 188		 Hempseed oil NASHM 4:1 12  >98% Caco-2 cell viability; increased uptake by 38.2% NA 62 0.032 > 99 [278]
Liposomes/
HSPC:DOPC:mPEG2000-DSPE		 Dox NASHM 9:1 10 Burst release (20–30%) followed by <10% release over 7 days at 37 °C or during 3 weeks storage at 4 °C Higher tumor accumulation (5–6% dose/g) at days 1 and 4. ~50 <0.2 > 80 [279]
Liposomes/
EPC or DMPC or DPPC or DSPC or PS:Chol		 OVA NASHM 3:1 15 Longer chain lipids have slower release rates; burst release observed within 12 h followed by a slower release rate NA 60–100 <0.2 20–35 [280]
Liposomes/
EPC:Chol		 Propofol NASHM 3:1 2 Burst release (40%,1 h) reaching 90% within 8 h NA ~40 0.4 85 [264]
Liposomes/DMPC:Chol:DEPE-PEG2000:DSPE-PEG2000—FA or DSPE-PEG2000-Cys-TAT(CYGRKKRRQRRR)
55:40:3:1 molar ratio 		Folic acid (FA) HFF 16:1 28.8 µL/min FA and TAT liposomes have 37% and 98% increased targeting in SKOV3 cell spheroids compared to TAT liposomes and FA liposomes, respectively Improved tumor targeting and longer tumor retention (up to 72 h); 140%, 136%, and 62% higher tumor accumulation than pegylated liposomes and FA or TAT targeted liposomes, respectively ~60 <0.3 NA [223]
Lipoplex/DSPC:cholesterol: DOTAB or DDAB or D-Lin-MC3-DMA:DMG-PEG2000, mRNA or ssDNA, Poly A NxGen 5:1–1:1 12−200 NA NA <100 <0.25 >90 [266]
Liposomes/HSPC:Chol:DSPE-PEG2000 56:38:5 molar ratio and EPC:Chol 45:55 molar ratio Dox M110P Microfluidizer® Pressures of 5–20 Kpsi 1–3 cycles NA NA 100–110 <0.2 97–98 [281]

Key: AmB: amphotericin B, BT-474: human ductal breast carcinoma cells, Chol: cholesterol, DCChol: 3β-[N-(N′,N′-dimethylaminoethane)carbamoyl] cholesterol, DDAB: DLin-MC3-DMA: (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino)butanoate, DLinKC2-DMA: 2-[2,2-bis[(9Z,12Z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-N,N-dimethylethanamine (ionizable cationic lipid), DMPC: 1,2-dimyristoyl-sn-glycero-3-phosphocholine, DPPC: 1,2-diplmitoylphosphatidylcholine, DODMA: 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane, DOL: dolomite microfluidic system equipped with a 5-input chip (part: 3200735, Dolomite, Royston, UK), DOPC: DOPE: l-α-dioleoyl phosphatidylethanolamine, DOTAP: 1,2-dioleoyl-3-trimethylammonium propane, DOTMA: N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride, DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine, DSPE-PEG2000: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt); DSPE-PEG2000-FolA: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000] (ammonium salt), DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine, DSPG: 1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol), Dox: doxorubicin, EPC: egg phosphatidylcholine, FF: flow focusing, HFF: hydrodynamic flow focusing, HSPC: hydrogenated soy l-α-phosphatidylcholine, ICU: isoprenylated coumarin umbelliprenin, LE: loading efficiency, NxGen: NxGen (Precision Nanosystems, CA, USA), MCF-7: human breast adenocarcinoma cells (hormone-positive), MDA-MB 231: human breast adenocarcinoma cells (triple-negative), mPEG-CHO: methoxy poly(ethylene glycol) aldehyde, mPEG: DMG: dimirystoyl-sn-glycero, methoxyethyleneglycol 2000 ether, mPEG2000-DSPC:1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000], NASHM: NanoAssemblr Benchtop with SHM, OVA: ovalbumin, PDI: polydispersity, PEG2000-C-DMA: N-[(methoxy poly(ethylene glycol)2000 carbamyl]-1,2-dimyristyloxlpropyl-3-amine, POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, PS: l-α-phosphatidylserine, SKOV-3 cells: human ovarian cancer cells, SHM: staggered herringbone micromixer, SPC: soy phosphatidylcholine, TAT cell-penetrating peptide sequence: CYGRKKRRQRRR, TF: transferrin, YSK05: 1-methyl-4,4-bis[(9Z,12Z)-9,12-octadecadien-1-yloxy]-piperidine (pH-sensitive cationic lipid).