Table 1.

Drug delivery approaches in IPF treatment models.

Drug	Dosage form; route of administration	Excipients; method of preparation	Characterization; In vitro/in vivo outcomes	Ref
Interleukin-10 (IL-10)	Hydrogel; intranasal administration	Heprasil and the crosslinker Extralink was mixed to for an in-situ hydrogel	IL-10 decreased the expression of fibrotic markers on treatment with TGFβ-1 activated fibroblasts.	[92]
AMD3100; siRNA	Nano-emulsion for intratracheal administration	Combination of fluorinated polymeric CXCR4 antagonist AMD3100 and siRNA; sonication method	In vitro cell culture assays suggested that siRNA decreased expression of α-SMA in fibrotic cells.	[93]
Nintedanib and colchicine	MMP-2 responsive peptide (peptide E5) modified liposomes; intravenous injection	Cholesterol, Soybean phospholipids, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol maleimide, 2000 Da (DSPE-PEG2K-Mal) and DSPE-PEG2K, peptide E5; thin film hydration	Peptide E5 modification improved the cellular uptake of liposomes and demonstrated synergistic effect.	[96]
Tetrandrine (TET)	TET encapsulated HP-β-CD inclusion nanosuspension complex for endotracheal administration	Hydroxy-propyl-β-cyclodextrin (HP-βCD); Kneading method	Study demonstrated the improved efficacy of inhaled TET inclusion complexes compared to intravenous administration of free TET.	[99]
Caveolin scaffolding domain peptide-7 (CSP7)	Excipient free micronized CSP7 peptide powder for inhalation delivery	Excipient free formulation formulated by micronizing of peptide power using airjet milling technology	Lung fibrosis in mice was significant reduced after treatment with CSP7 inhalation powder though nose-only inhalation exposure system.	[104]
Thymoquinone (TQ)	PLGA-PVA NPs; intratracheal administration	PVA; double emulsion method using probe sonicator	Developed NPs showed significant reduction in fibrosis in rats when compared with disease control group	[94]
Combination of astaxanthin (AST) and trametinib (TRA)	Monocyte-derived multipotent cell (MOMC) surface-engineered NPs (PER NPs); intravenous injection	Peptide E5, poly (lactide-co-glycolide) block-poly (ethylene glycol) methyl ether maleimide (PLGA-PEG-Mal) and PLGA-PEG-c (RGDfc), Monocyte-derived multipotent cell (MOMC) isolated from rat blood; antisolvent precipitation method	Developed surface modified dual drug loaded PLGA NPs showed better antifibrotic activity then a current clinically USFDA approved drug – Pirfenidone.	[106]
Pirfenidone	CHI-SA NPs loaded with PFD as efficient transdermal drug delivery system	Pre-gelation method used to synthesize Chitosan and Sodium Alginate polymeric NPs	Release profile of the CHI-SA NPs showed sustained release of PFD from synthesized NPs. Fluorescent microscope images of PFD loaded CHI-SA NPs showed that NPs transfer through skin successfully.	[107]
Inhaled treprostinil prodrug hexadecyl-treprostinil (C16TR) formulated in a lipid NP (INS1009)	Lipid NP for delivery by nebulization; INS1009 was given by nose-only inhalation	INS1009 was formulated at a stock concentration of 0.3 mg/mL in PBS and appropriate dilutions were prepared to achieve the target doses	Evaluating anti-fibrotic effects through therapeutic dosing in a rat model of bleomycin-induced pulmonary fibrosis. Treatment of rats with inhaled INS1009 produced robust and dose-dependent reductions in the lung hydroxyproline content.	[108]
Fluorofenidone (AKF; 5-methyl-1-[3-fluorophenyl]-2-[1H]-pyridone)	Spermidine (Spd)-modified PEG-PLGA NPs as a lung-targeted delivery system for AKF; Both Spd-AKF-PLGA NPs and AKF-PLGA NPs were distributed to lung after intravenous injection.	Carboxylate-functionalized copolymer PLGA-PEG-COOH was synthesized by conjugating COOH-PEG-NH2 to PLGA-COOH. Emulsification-solvent evaporation was employed for the preparation of AKF NPs.	Biodistribution study suggested that Spd-AKF-PLGA NPs accumulated effectively in the lung. Fluorescence analysis showed that the Spd-AKF-PLGA NPs had high affinity for A549 cells and facilitated endocytosis.	[109]
Tacrolimus	Nebulized Tac-NPs or Tac by I.P. injection; Inhalation via a nose-only dosing chamber	Liquid dispersion of colloidal Tac and lactose aerosolized used vibrating mesh nebulizer	In vivo; Higher survival with inhaled Tac vs. injected Tac and reduced inflammation and fibrosis	[97]
Tacrolimus	60 μ Tac; Intratracheal instillation via microspray aerosolizer	Tac (2.5mg) and cholesterol (5mg) dissolved in .1ml of 9:1 solution of chloroform and ethanol; BSA (50mg) dissolved in 5 ml deionized water; high-pressure homogenizer nine times at 20,000psi; rotary evaporated and centrifuged	In-vivo; Promising therapeutic efficacy	[110]
Tacrolimus	180 μ Tac twice a week; Direct inhalation	O/w emulsification diffusion method to prepare tacrolimus-loaded chitosan-coated poly (lactic-co-glycolic acid) NPs	In-vivo; Better efficacy than oral administration daily	[98]
Montelukast (montelukast loaded nanostructured lipid carriers (MNLC))	5 mg montelukast for in vitro; equivalent of 1 mg aerosolized for in vivo; Intratracheal instillation	Melt-emulsification-ultrasonication method; prepared with 3% mannitol	In vivo and in vitro; MNLC-DPI improved drug deposition in lungs; high potential for pulmonary targeting	[111]