Table 1.
Comparative table summarizing all forms of IFN-α, IFN-β, and IFN-γ delivery systems described in the scientific literature from 1996 to March 2021.
| IFN Type | Encapsulating Matrix | Route of Administration | Encapsulation Method | Physical Properties | Formulation Objective | Advantages/Disadvantages | Ref. |
|---|---|---|---|---|---|---|---|
| IFN-α | Microspheres of LEAVE |
In vitro | Double emulsion/solvent evaporation | Size = 186 µm | Stabilization of IFN-α on PELA particles with sustained release and retention of antiviral activity for up to 11 days in in vitro studies. | A: stabilization of IFN in the matrix D: initial burst release |
[119] |
| PLGA microspheres | In vitro | Double emulsion/solvent evaporation | Size = 1.8 µm | Sustained in vitro release of methoxy-PEG-IFN-α for up to 3 weeks, although they exhibited high release peaks. | A: solubility maintained D: initial burst release |
[120] | |
| PLGA/ poloxamer |
In vitro | Oil-in-oil solvent extraction | Size = 40 µm | Evaluation of microparticles and nanoparticles as an in vitro controlled release system. The MPs released IFN for up to 96 days. | A: integrity and activity of the molecule D: initial burst release |
[54] | |
| Multivesicular liposomes | In vitro | Double emulsion/solvent evaporation | Size = ~20 µm | Development of a system for controlled and sustained release of PEG-IFN-α for up to 6 days in vitro. | A: high stability and encapsulation efficiency D: initial burst release |
[101] | |
| Uni- and multivesicular liposomes | Intramuscular | Film hydration-dilution | Size = 101 nm | Prolonged retention of IFN-α-2b for up to 24 h at the application site after intramuscular administration in Kungming mice. | A: high retention at the application site D: loss of activity |
[102] | |
| Lysine-coated gold nanoparticles | In vitro | Chloroauric acid and borohydride reduction | Size without IFN = 10 nm | in vitro transport of IFN-α on gold nanoparticles coupled to lysine found on the particle surface. | A: stable conjugation in water D: modification of the carboxyl groups of the molecule |
[145] | |
| Poly(ether-ester) microspheres (Poly-Active) | Subcutaneous | Double emulsion/solvent evaporation | Size = ~30 µm | Phase IIB clinical study of Locteron®, a 14-day dose–response sustained-release formulation, well tolerated by patients at a dose of 80 µg. | A: significant decrease in adverse events D: scarce report of its physicochemical characterization |
[121] | |
| PLGA microspheres | In vitro | Double emulsion/solvent evaporation | Size = 28.1 µm | Encapsulation of IFN-α in PLGA microparticles in vitro. No changes were detected in the physicochemical and biological characteristics of the molecule released by diffusion for 24 h at 37 °C. | A: uniform size distribution D: IFN instability |
[127] | |
| PLGA microspheres | Intramuscular | Double emulsion/solvent evaporation | Size = 81.23 µm | Increased residence time of IFN-α in serum up to 18 days, and sustained release with activity up to 12 days in studies in rhesus monkeys. | A: increase in circulation time in vivo D: loss of biological activity |
[128] | |
| Alginate microspheres chitosan |
Intramuscular | Coacervation | Size = 2.18 µm | Evaluation of pharmacokinetics in ICR mice, revealing a 4-fold increase in the half-life of IFN-α, with no increased peak concentration, and reduced bioavailability | A: increase in maximum serum concentration D: low encapsulation efficiency |
[129] | |
| PLA and PLGA microspheres | In vitro | Double emulsion/solvent evaporation with magnetite nanoparticles inclusion | Average size = 2.5 µm Size distribution = 0.5–3.5 µm |
Particle loading with magnetite for site-specific delivery. In vitro antiviral assays in Vero cells against vesicular stomatitis virus indicated a slight reduction in the antiviral activity of the particles. | A: particle direction using magnetic field D: low encapsulation efficiency |
[130] | |
| PLGA microspheres | In vitro | Double emulsion/solvent evaporation | Size distribution = 40.54–115.62 µm | Sustained release maintains the molecule’s biological activity for up to 7 days in in vitro studies in Wish cells against vesicular stomatitis virus. | A: high encapsulation efficiency D: in vivo performance was not evaluated. |
[131] | |
| IFN-α | PLGA-PEGT/PBT microspheres | Subcutaneous | Double emulsion/solvent evaporation | Size = 28.94 µm | Extended cumulative release for up to 23 days in vitro, conforming to zero-order kinetics. Plasma levels were stable for 13 days in Sprague–Dawley rats, starting with a rapid release on day 1. | A: high encapsulation efficiency D: initial burst release |
[132] |
| PLGA nanoparticles with adsorbed HBV antigens | Intravenous | Double emulsion | Size = 174 nm PZ = +30 mV |
System aimed at treating hepatitis B. Studies in BALB/c mice indicated that nanoparticles transport IFN to hepatocytes, with good systemic circulation. | A: site-specific transport D: low encapsulation efficiency |
[148] | |
| Liposomes | Intramuscular | Film hydration | Size = 82–172 nm PDI < 0.35 |
Increased half-life, peak time, and bioavailability of encapsulated IFN-α-2b in Wistar rats. | A: accumulation in the liver D: non-uniform size |
[103] | |
| Gold nanoparticles plus hyaluronic acid (HA) | Intravenous | Chloroauric acid reduction with citrate and reductive amination of HA | Size = 52.23 nm PDI = 0.089 |
Selective transport to the liver for HCV treatment. Biological activity of IFN-α is similar to PEG-Intron in vitro (Daudi), in vivo (BALB/c mice). | A: serum stability D: slow initial release |
[146] | |
| Protamine sulfate-impregnated gelatin microspheres | In vitro | Emulsion polymerization with glutaraldehyde as a crosslinker | Size = 28.94 µm | Protamine sulfate impregnation to increase the release time of IFN-α to 336 h and prolong the cytotoxic effect in vitro in ovarian cancer Skov3 cells | A: almost complete release D: no correlation with cytotoxicity |
[133] | |
| Chondroitin sulfate and PVP | Intradermal | Two-solution system in polydimethylsiloxane molds | Arrangements of 12 × 12 microneedles. Dimensions: 680 × 380 μm |
Transport of IFN-α in microneedles. In vivo studies (SD rats), the needles have good stability for two months and do not cause skin damage. | A: no injections required D: limited stability over time |
[134] | |
| PLGA and PEG-PLGA nanoparticles | In vitro | Double emulsion/solvent evaporation | Size = 104–129 nm | Evaluation of sustained release of IFN-α under in vitro conditions: phosphate-buffered saline and blood plasma. | A: sustained and stable release D: in vivo pharmacokinetics not evaluated. |
[149] | |
| Chitosan nanoparticles | Evaluation of the oral route | Ionotropic gelation | Size = 36 nm PZ = +30 mV |
Nanoparticles for oral administration, with in vitro antiviral activity (MDBK) comparable to commercial IFN-α. IFN levels in plasma 1h after in vivo inoculation (in CF-1 mice). | A: high encapsulation efficiency D: non-specific release in the stomach |
[150] | |
| PEGylated Liposomes | Franz Cell Diffusion System | Film hydration | Size = 181 nm PZ = −13 mV |
Formulation for treatment of human papillomavirus. No in vitro release. Ex vivo studies in goat vaginal tissue with high penetration of the molecule into the tissue. | A: crosses mucosa D: in vitro and ex vivo release was not correlated |
[105] | |
| POEGMA-PHPMA copolymer micelles | Intravenous | Self-assembly of copolymer blocks | Size = 64.9 nm | Formation of micelles by self-assembled copolymer blocks that encapsulated IFN-α, with increased half-life up to 83.8 h, and antitumor activity in mice with ovarian tumors | A: effective tumor suppression D: decrease in biological activity |
[57] | |
| Chitosan nanoparticles | Oral | Ionotropic gelation | Size = 36 nm PDI = 0.47 Potential Z = +30 mV |
Evaluation of oral administration of nanoparticles. In vitro (Caco-2:HT29-MTX (9:1)) and in vivo (BALB/c mice) studies confirmed improved pharmacokinetics and bioavailability. | A: crosses intestinal epithelium D: no analysis in disease models |
[151] | |
| Core-shell nanoparticles; core: HSA-IFN-α, shell: PSS-CS-PSS | Subcutaneous | Core: aqueous precipitation; shell: layer-by-layer assembly | Size = 100 nm PZ = −50 mV |
Sustained-release after ten days in Pannon rabbits, with biological activity similar to lyophilized HSA-IFN-α. | A: bioactivity maintained D: PSS is not biocompatible |
[152] | |
| Elastin-like copolypeptide micelles | Intravenous | Self-assembly of two copolypeptide building blocks | Size = 48 nm | Formation of micelles by blocks of two self-assembled polypeptides that encapsulated IFN-α, with an increase in its half-life up to 54.7 h, and antitumor activity in mice with ovarian tumors. | A: efficient accumulation in tumors D: encapsulation efficiency is not reported. |
[58] | |
| IFN-β | Poly(methacrylic acid-ethylene glycol) microparticles | Direct intestinal | UV polymerization using TEGDMA as crosslinker | Size < 53 µm | Encapsulation for intestinal delivery of IFN-ß. In vitro and in vivo results in Sprague–Dawley rats showed sustained release and improved pharmacokinetics. | A: pH-sensitive behavior D: incomplete release |
[135] |
| TMC-PEGDMA-MAA microparticles | Oral | Suspension polymerization by free radicals | Size = 1–3.5 µm at intestinal pH (6.8) | pH-sensitive oral transport system for the treatment of multiple sclerosis. Most of the IFN-ß was released in vitro at intestinal pH. Release profile in New Zealand White rabbits exceeded 24 h. | A: pH-sensitive D: in vitro and in vivo release was not correlated |
[136] | |
| PLGA and PEG-PLGA nanoparticles | Subcutaneous | Double emulsion/solvent evaporation | Size = 145 nm and 163 nm PZ = 17.7 and 18.8 mV |
Treatment of Multiple Sclerosis. No toxicity in vitro, in vivo studies in Wistar rats showed mild toxic effects such as pale kidney and pyelectasis. | A: high encapsulation efficiency D: mild toxicity |
[153] | |
| Chitosan nanoparticles/cyclodextrin | Intranasal | Gelation | Size = 206 nm PZ = 20 mV PDI = 0.13 |
Nasal administration of the formulation for treating multiple sclerosis, with greater effectiveness, than free IFN-β in C57BL/6 mice with sclerosis. | A: reduction in encephalomyelitis D: no CD4+ lymphocyte downregulation |
[154] | |
| IFN-γ | PLGA microspheres | In vitro | Double emulsion/solvent evaporation | Size = 30–50 µm | Stabilization of IFN-γ in microparticles, maintaining the native conformation and biological activity of the protein. | A: bioactivity maintained D: encapsulation destabilizes the protein |
[137] |
| PLA microspheres | Oral | Double emulsion/solvent evaporation | Size = 1.27 µm | Sustained release in vitro for 400 h and increased absorption when administered orally in Wistar rats. | A: increase in porosity D: delayed release |
[138] | |
| Liposomes | Inhalation | Freezing, thawing | Size = 170–180 nm | It demonstrated that encapsulation of IFN-γ and liposomal muramyl tripeptide with chitosan activated alveolar macrophages and increased survival in the treated group. In vivo study in a murine model. | A: increase in the activation of alveolar macrophages. D: loss of biological activity |
[97] | |
| BSA nanoparticles | Intraperitoneal | Coacervation and chemical crosslinking | Size = ~340 nm PZ = −19.6 mV |
Evaluation of macrophage activation for Brucella abortus. It increased the bactericidal effect of IFN-γ-activated macrophages in vitro and in vivo (BALB/c mice). | A: increased biological activity D: extended-release only for 20 h |
[155] | |
| Liposomes with cyclic peptides | Intravenous | Film hydration | Size = 83.5 nm PDI = 0.067 |
Selective liposome transport to hepatic stellate cells increased half-life and antifibrotic activity of IFN-γ with fewer adverse effects in Sprague–Dawley rats. | A: selective transport to hepatic cells D: low encapsulation efficiency |
[104] | |
| PLGA core–shell nanoparticles containing IFN-γ and doxorubicin. | Intravenous | Nanoprecipitation | Size = ~100 nm | Melanoma immunotherapy. Female C57BL/6 murine model, free IFN at 8 h, encapsulated cleared after 48 h inoculated in mice. There was no toxicity in vital organs. | A: temperature-sensitive behavior D: conditional encapsulation efficiency |
[156] | |
| PEGylated Liposomes | Intravenous | Thin-film hydration and extrusion | Size = 135 nm PDI = 0.05 |
Preparation of IFN-γ-containing liposomes for colon cancer treatment. Sustained release in vitro for 144 h with an abrupt onset and increased cytokine-activated antitumor immune response in BALB/c mice with C-26 tumor cells. | A: significant induction of the antitumor response D: low encapsulation efficiency |
[106] |