Table 3.
Liposomes, ethosomes, cubosomes, and hybrid liposomal nanocarriers for ARV delivery.
| Year | Composition | ARV | Physicochemical Characterization | Outcomes | Ref. | |||
|---|---|---|---|---|---|---|---|---|
| E.E. (%) | D.L. (%) | ζ-Potential (mV) | Size (nm) | |||||
| Liposomes | ||||||||
| 1990 | DOPC:DPPG:Chol:Triolein (5:1:8:1) |
ddC e logP = −1.35 |
48.3 ± 2.6 | N.D. | N.D. | 39,600 ± 11,900 | ↑ residence time in CNS ↑ controlled release |
[91] * |
| 1991/92 | DPPC:DMPG (10:1) or DSPC:DMPG (10:1) |
AZT a logP = 0.05 |
N.D. | LP w/DPPC: 9.35 ± 0.45 LP w/DSPC: 8.98 ± 0.56 |
N.D. | N.D. | ↑ ARV activity ↓ hematopoietic toxicity |
[57,68] * |
| 1994 | DSPC:DSPG (10:3) | ddI a logP = −1.24 |
85 ± 15 | 21 ± 1 | N.D. | 180 ± 20 | ↑ bioavailability ↓ systemic exposure ↓ effective fighting the virus compared to free ddI |
[69] *,** |
| 1995 | DPPC:DCP:Chol (4:1:5) | ddC logP = −1.35 |
N.D. | 35 | N.D. | 300 | ↑ ddC retention in macrophages | [92] ** |
| 1996 | DSPC:DSPG (10:3) or DSPC:DSPG:DSPE-PEG (10:3:1.45) |
ddI a logP = −1.24 |
N.D. | 26 ± 4 | N.D. | 150 ± 10 | Better pharmacokinetic profile ↑ viral reservoirs targeting ↑ bioavailability |
[17]*,** |
| 2000 | EPC, DMPG, SM, DMPC, DPPC, DSPC, DMPC:Chol (4:1; 2:1 and 1:1), DSPC:Chol (4:1; 2:1 and 1:1), DPPC:Chol (2:1), DPPC:Chol:PS (6:3:1), DPPC:Chol: DCP (6:3:1) | d4T logP = −0.72 |
35 to 50 | N.D. | +, − and neutral charges | 600 to 1400 | ↑ maximal uptake by DPPC liposomes in macrophages and monocytes ↑ uptake with negative charged liposomes |
[93] ** |
| 2002 | DPPC:DPPG:DSPE-PEG-MAL (10:3:0.83) | IDV g logP = 2.9 |
11 ± 4 | N.D. | N.D. | 100 to 120 | ↑ [IDV] to lymphoid tissues | [94] * |
| 2003 | EPC:Chol (3:1) | IDV g logP = 2.9 |
97.5 ± 2.5 at pH 7.4 ≈ 20 at pH 5.5 |
19.5 ± 0.5 at pH 7.4 ≈4 at pH 5.5 |
N.D. | 69 ± 7 | ↑ CD4+ T cells ↓ viral load in lymph nodes and plasma |
[95] * |
| 2005 | SPC:AZT-M:VE (6:2:0.1) | AZT-M a | Liophilization Before: 99.4 ± 0.8 After: 98.3 ± 1.2 |
N.D. | - charges | Liophilization Before:88.5 ± 4.5 After:89.6 ± 6.3 |
↑ [ARV] in organs of RES and brain | [81] * |
| 2006 | EPC:Chol:SA (7:2:1) Uncoated LP or coated w/OPM: OPM-LP |
d4T a logP = −0.72 |
Uncoated LP: 49.6 ± 1.2 OPM-LP: 47.2 ± 3.3 |
N.D. | Uncoated LP: + charge OPM-LP: charges ↓ close to neutrality |
Uncoated LP: 120 ± 1.5 OPM-LP: 140 ± 2.3 |
↑ targeting ↑ residence time in HIV viral reservoirs ↑ d4T half-life ↑ pharmacological activity ↑ distribution ↓ elimination |
[13] *,** |
| 2007 | EPC:Chol:DMPE (7:2:1) Uncoated LP or coated w/OPG: OPG-LP |
d4T a logP = −0.72 |
Uncoated LP: 46.2 ± 0.69 OPM-LP: 47.1 ± 1.2 |
N.D. | Uncoated LP: +8.21 ± 0.15 OPG-LP: +3.2 ± 0.21 |
Uncoated LP: 122.3 ± 0.3 OPM-LP: 129.5 ± 0.3 |
↑ d4T half-life ↑ residence time ↑ hepatic cellular d4T uptake |
[14] *,**,*** |
| 2008 | EPC:Chol:DMPE (7:2:1) Uncoated LP or coated w/OPG: OPG-LP |
d4T a logP = −0.72 |
Uncoated LP: 49.6 ± 1.2 OPG-LP: 48.7 ± 0.2 |
N.D. | N.D. | Uncoated LP: 120 ± 4 OPG-LP: 126 ± 4 |
Inhibition of HIV p24 protein with uncoated LP and OPG-LP ↑ accumulation of OPG-LP in the liver, spleen, and MPS ↓ uptake of OPG-LP in bone |
[96] *,** |
| 2006 | EPC:Chol:PE (7:2:1) Uncoated LP or coated w/OPG: OPG-LP) |
AZT a logP = 0.05 |
Uncoated LP: 54.3 ± 3.3 OPG-LP: 53.9 ± 2.1 |
N.D. | Uncoated LP: + charge OPM-LP: charges ↓ close to neutrality |
Uncoated LP: 120.0 ± 2.1 OPG-LP: 136.9 ± 1.9 |
↑ AZT half-life ↑ residence time ↑ bioavailability |
[15] *,** |
| 2006 | SPC:Span80® (85:15) SPC:PEG-8-L (85:15) |
AZT c logP = 0.05 |
LP w/Span80®: 63.5 ± 2.9 LP w/PEG-8-L: 57.1 ± 3.1 |
N.D. | LP w/Span80: −2.8 ± 0.4 LP w/PEG-8-L: −16.7 ± 0.7 |
LP w/Span80®: 132 ± 15 LP w/PEG-8-L: 116 ± 10 |
Better pharmacokinetic profile ↑ accumulation of AZT in target RES organs ↑ AZT half-life ↑ residence time, targeting, and controlled release |
[19] *,** |
| 2007 | DPPC Note: intended for oral administration |
ddI logP = −1.24 |
N.D. | N.D. | N.D. | 1160 ± 129 | ↑ bioavailability | [97] ** |
| 2007 | PC:POPG (3:1) | IDV logP = 2.9 SQV logP = 3.8 |
N.D. | N.D. | N.D. | 130 to 150 | ↑ liposomal solubilization of both drugs ↑ drug concentration in the media (10- and 750-fold for IDV and SQV, respectively) |
[98] ** |
| 2008 | Plain-LP: SPC:PE:Span 80 (42.5:42.5:15) PEG-LP: SPC:PE:Span 80:MPEG 2000 (42.5:42.5:15:33.3) |
AZT c logP = 0.05 |
Plain-LP: 63.5 ± 2.9 PEG-LP: 72.3 ± 4.5 |
N.D. | Plain-LP: −2.8 ± 0.4 PEG-LP: −18.2 ± 0.8 |
Plain-LP: 132 ± 14 PEG-LP: 158 ± 15 |
↑ cellular uptake in lymphoid cells ↑ biodistribution ↑ residence time and sustained drug release |
[53] *,** |
| 2008 | LP: SPC:Chol (7:3) + charge LP: SPC:Chol:SA (7:3:1) - charge LP: SPC:Chol:DCP (7:3:1) w/Mannose: SPC:Chol:Man (7:3:2.5) |
AZT g logP = 0.05 |
LP: 18.5 ± 1.2 + charge LP: 24.2 ± 0.9 − charge LP: 22.4 ± 1.4 Man-LP: 20.0 ± 2.5 |
N.D. | LP: +10.3 ± 1.8 +charge LP: +54.4 ± 2.3 −charge LP: −34.8 ± 4.45 Man-LP: +14.7 ± 3.9 |
LP: 122 ± 6 + charge LP: 126 ± 3 − charge LP: 128 ± 4 Man-LP: 127 ± 1.2 |
↓ release in Man-LP as compared to LP ↑ uptake ↑ localization of Man-LP in the lymph nodes and spleen |
[99] *,** |
| 2009 | HSPC:Chol:mPEG–DSPE (55:40:5) | PI1 | N.D. | N.D. | N.D. | N.D. | ↑ and longer antiviral activity Facilitated specific uptake by non-phagocytic HIV-infected cells |
[100] ** |
| 2010 | EPC:Chol (9:1) | NVP logP = 2.5 |
78.1 | 7.81 | N.D. | <200 | ↑ E.E. Quick in vitro release from liposomes |
[101] ** |
| 2011 | DPPC | ProddINP b logP = 0.05 |
99 | 8.83 | −0.8 ± 0.5 | 187 to 208 | ↑ ddI blood half-life (3-fold) ↑ accumulation as prodrug at 24 h in various organs compared to plain drug |
[79] *,** |
| 2011 | DPPC:EDPPC (1:1) | SFV logP = −19.5 |
N.D. | N.D. | N.D. | N.D. | Strong affinity of SFV for DPPC:EDPPC ↑ Affinity with ↑ cationic EDPPC Fusion w/viral/raft-mimicking vesicles |
[102] ** |
| 2011 | Chol:SA (194:1; 39:1; 22:1; 16:1;4:1) w/Span 20®/Span 40®/Span 60® | TFV logP = −1.6 |
3.46 to 65.26 | N.D. | +4.79 to +17.13 | 36.13 to 114.9 | The composition had a significant impact on TFV release Size and ζ were inversely proportional to the homogenization parameters, in contrast to the E.E. and conductivity TFV distributed within both the aqueous and lipid phases |
[103] ** |
| 2012 | EPC:DSPE-PEG | SQV logP = 3.8 |
32.2 ± 2.9 | N.D. | −35.50 ± 1.66 | 176.6 ± 6.8 | ↓ cytotoxicity with PEGylated liposomes | [104] ** |
| 2012 | DMPC:Chol:DPTAP (55:27:18) DPPC:Chol:DPTAP (55:27:18) DSPC:Chol:DPTAP (55:27:18) DSPC:Chol:SA (60:30:10) |
TFV logP = −1.6 |
N.D. | N.D. | DMPC:Chol:DPTAP: +71.11 ± 5.72 DPPC:Chol:DPTAP: +62.50 ± 2.64 DSPC:Chol:DPTAP: +59.76 ± 2.49 DSPC:Chol:SA: +31.54 ± 1.90 |
DMPC:Chol:DPTAP: 166.8 ± 18.1 DPPC:Chol:DPTAP: 158.1 ± 32.0 DSPC:Chol:DPTAP: 159.0 ± 35.5 DSPC:Chol:SA: 158.5 ± 34.7 |
In the two-stage reverse dialysis method proposed, no drug leakage occurred during the 1st stage in LP containing high phase transition temperature lipids and high Chol content In the 2nd stage, significant differences in TFV release rate occurred in LP with different compositions |
[105] ** |
| 2010/13 | Chol:Phospholipon 100H:SA (1:1:0; 5:5:1; 3:3:1; 2.3:2.3:1; 2:2:1; 2:1:1) |
TFV. logP = −1.6 |
1.28 ± 0.24 (1:1:0) to 70.8 ± 2.55 (2:1:1) | 0.39 ± 0.087 (1:1:0) to 17.71 ± 1.87 (2:1:1) | −3.43 (1:1:0) to +93.5 (5:5:1) | 46.6 (1:1:0) to 2,200 (2:1:1) | ↑ permeation of TFV (Caco-2 cell model) | [106,107] ** |
| 2016 | LP DSPE:Stearic Acid:Chol (1:1:1) Stealth LP DSPE:Stearic Acid:Chol w/PEG 10000 |
RTV a logP = 3.9 |
LP: 98 ± 0.5 Stealth LP: 94.12 ± 0.29 |
LP: 11.92 ± 0.06 Stealth LP: 11.45 ± 0.03 |
LP: −33 ± 0.4 Stealth LP: −43.6 ± 1.8 |
LP: 49 ± 0.3 Stealth LP: 116.6 ± 0.1 |
Stealth LP prolongs RTV release to 34 h ↑ half-life of RTV for stealth LP LP and pure RTV showed dose dependent pharmacokinetics |
[80] *,** |
| 2017 | Phospholipon 100H:Chol:SA (3:3:1 and 2:2:1) Note: intended for oral administration |
TFV logP = −1.6 |
(3:3:1): 39.8 ± 8.1 (2:2:1): 68.1 ± 2.6 |
N.D. | + charge | N.D. | ↑ cellular permeability (10 times higher) ↑ E.E. |
[108] ** |
| 2017 | HSPC:Chol (7:3) | LPV b logP = 5.94 |
90.47 ± 0.32 | N.D. | −24.8 ± 0.21 | 659.7 ± 23.1 | ↑ LPV release at 60 min (95% for LPV loaded proliposomes vs. 55% for free LPV) ↑ intestinal permeation (≈1.99 fold) compared to pure LPV) ↑ oral bioavailability (2.24- and 1.16-fold) than pure LPV and commercial LPV/RTV, respectively. |
[109] *,**,*** |
| 2015 | EPC:Chol:DSPE-PEG (9:1:1) | NVP logP = 2.5 and SQV logP = 3.8 |
NVP: 44 ± 2 SQV: 44 ± 1 |
N.D. | −29 ± 2 | 160 ± 2 | ↑ inhibition of viral proliferation at lower doses compared to free drugs NVP is mainly released in the early phases and SQV in the later phases of infection |
[70] ** |
| 2017 | SPC:Chol (2:1) Plain or coated w/biotin |
RTV b logP = 3.9 |
Plain LP: 62.3 ± 1.7 Biotin-LP: 61.6 ± 1.8 |
N.D. | Plain LP: −18.9 ± 2.0 Biotin-LP: −26.1 ± 2.5 |
Plain LP: 126.6 ± 6.2 Biotin-LP: 149.8 ± 6.8 |
↑ release from biotin coated liposomes compared to conventional ones ↑ [RTV] in lymphatic tissues |
[110] *,** |
| 2018 | DSPC:DSPE-mPEG2000 (9:1) | ATV g logP = 4.5 RTV logP = 3.9 TFV logP = −1.6 |
ATV: 99 ± 8.2 RTV: 92 ± 7.1 TFV: 10 ± 0.8 |
N.D. | N.D. | 6 to 62 | ↑ residence time in plasma and peripheral blood mononuclear cells | [21] * |
| 2019 | DPPC Note: intended for vaginal administration |
TDF logP = 2.65 FTC logP = −0.43 |
84 | 1 | Zwitterio-nic | 134 ± 13 | ↑ TDF permeation and ↑ sustained release Non-cytotoxic in CaSki (epidermoid cervical cancer cell line) and HEC-1-A (Human Endo-metrial Cancer-1) |
[52] ** |
| 2020 | POPC POPC:DPPE-PEG2000 (9:1) |
T20 logP = −14.7 PPI xT20 + PPIX |
N.D. | N.D. | Zwitterio- nic charge was predominantly affected by PPIX |
Unloaded POPC: 110 nm Unloaded POPC:DPPE-PEG2000 (9:1): 120 nm Size was affected by PPIX |
↑ entry inhibitors (T20 and PPIX) synergy compared to combination in free aqueous form | [111] ** |
| Ethosomes | ||||||||
| 2007 | SPC w/ethanol | 3TC c logP = −1.4 |
57.2 ± 4.1 | N.D. | −8.2 ± 1.5 | 102 ± 13 | ↑ cellular uptake ↑ transdermal flux (25 times higher) ↑ elasticity contributes to enhanced skin permeation |
[112] *,*** |
| Cubosomes | ||||||||
| 2021 | GMO:CTAB:poloxamer 407(245:9:1, 219:9:1) | ATV g logP = 4.5 |
61 ± 4.6 (219:9:1) to 93 ± 1.2 (245:9:1) |
N.D. | −29.41 (219:9:1) to −24.53 (245:9:1) |
253 ± 5.6 (219:9:1) to 150 ± 8.7 (245:9:1) |
↑ATV absorption and bioavailability (4.6 folds) compared to oral administration ↑ transdermal drug permeation due to bio-adhesive characteristic and permeation enhancement effect |
[113] *,**,*** |
| 2020 | GMO:CTAB: poloxamer 407 (18:15:1) | SQV b,d logP = 3.8 |
72 ± 2 higher concentrations of GMO favored drug entrapment |
N.D. | N.D. | 120 ± 2 ↑ particle size with ↑ GMO and ↓ Poloxamer 407 |
↑ SQV bioavailability (12-fold and 2.5-fold) when compared with oral and intranasal administration of free SQV | [114] *,*** |
| Hybrid liposomal nanocarriers | ||||||||
| 2017 | SPC and gelatin nanoparticles (SG-LP) | d4T logP = −0.72 |
Gelatin NP (SG): 56.0 ± 1.7 SG-LP: 55.1 ± 2.1 |
N.D. | SG-LP: −44.6 ± 1.36 |
SG-LP: 232.9 ± 1.5 |
↑ controlled release ↑ uptake and hemocompatibility ↑ d4T half-life ↓ blood viremia |
[20] ** |
| 2017 | LP DPPC or DPPC:Chol (1:1, 4:1, 2:1) Magneto-plasmonic LP MNP@Au coated w/PEG |
TDF logP = 2.65 |
↑ E.E. w/higher drug ratio (≈30% for LP:TDF (1:34)) ↑ E.E. w/smaller Chol content (≈60% for DPPC) |
N.D. | N.D. | ↓ with increasing Chol | ↑ TDF release for LP without Chol ↑ transmigration across an in vitro BBB model by magnetic targeting ↓ viral replication of HIV infected microglial cells |
[115] ** |
| 2010 | LP SPC:Chol (1.2:1) Magnetic LP LP + magnetic AZTTP NP |
AZTTP | 54.5 ± 6 | N.D. | N.D. | ∼150 nm | ↑ permeability (3-fold) for magnetic AZTTP LP than free AZTTP Efficient taken up by monocytes ↑ transendothelial migration in presence of an external magnetic field compared to normal/non-magnetic monocytes |
[116] ** |
| 2021 | LP DMPC:DOPE:Chol (7:2:1) inside PVA nanofibers |
TDF h logP = 2.65 FTC logP = −0.43 |
100 | 4 (FTC) and 2.8 (TDF) | LP −0.67 ± 0.01 |
211 ± 24 | Rapid onset of local drug levels upon single vaginal administration of fibers to mice comparing to the continuous daily use for 5 days of oral TDF/FTC Drug concentrations in vaginal fluids were fairly sustained up to 1–4 h, which could be translatable into a quite wide protection time window in humans |
[117] * |
Notes: a intravenous injection; b oral administration; c transdermal administration; d intranasal administration; e intraventricular administration; g subcutaneous injection; h vaginal administration; N.D. no data * in vivo studies performed; ** in vitro studies performed; *** ex vivo studies performed. Abbreviations: 3TC, lamivudine; ARV, antiretroviral; ATV, atazanavir; Au, gold; AZT, zidovudine; AZT-M, zidovudine myristate; AZTTP, azidothymidine 5′-triphosphate; BBB, blood-brain barrier; CaSki, epidermoid cervical cancer cell line; Chol, cholesterol; CNS, central nervous system; CTAB, cetyltrimethylammonium bromide; d4T, stavudine; DCP, dicetyl phosphate; ddC, zalcitabine; ddI, didanosine; DMEM, Dulbecco’s Modified Eagle’s Medium; D.L., drug loading; DLMA, inner uncoated liposomes; DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPE, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol); DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; DPPE-PEG2000, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]; DPPG, 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol); DPTAP, 1,2-dipalmitoyl-3-trimethylammonium-propane (chloride salt); DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; DSPE, 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine; DSPG, 1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol); EDPPC, cationic 1,2-dipalmitoylethyl-phosphatidylcholine; E.E., entrapment efficiency; EPC, egg phosphatidylcholine; FTC, emtricitabine, Gal-DLMA, inner galactosylated liposomes; Gal-DMPE, galactosylated phosphatidylethanolamine; GMO, glyceryl monooleate; HEC-1-A, human endometrial cancer-1; HIV, human immunodeficiency virus; HSPC, hydrogenated soy phosphatidylcholine; IDV, indinavir; logP, partition coefficient; LP, liposome; LPV, lopinavir; MAL, maleimide; Man, mannose; MCZ, miconazole nitrate; MPEG 2000, mono methoxy PEG 2000; mPEG, methoxyl poly(ethylene glycol); MNP, magnetic nanoparticles; MPS, mononuclear phagocyte system; N.D., no data; NP, nanoparticles; NVP, nevirapine; OPG, O-palmitoylgalactose; OPM, O-palmitoylmannose; PBS, phosphate buffered saline; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEG, polyethylene glycol; PEG-8-L, octaoxyehtylene laurate ester; PLPC, 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPE, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol); PPIX, protoporphyrin IX; ProddINP, glycerolipidic prodrug of ddI; PS, phosphatidylserine; PVA, poly(vinyl alcohol); RES, reticuloendothelial system; RTV, ritonavir; SA, stearylamine; SFV, sifuvirtide; SM, sphingomyelin; SPC, soy phosphatidylcholine; SQV, saquinavir; T20, enfuvirtide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; VE, α-tocopherol.