Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

Figures & data

Figure 1 Time course of discovery of antifungal drugs.

Abbreviations: ABLC, amphotericin B lipid complex; ABCD, amphotericin B colloidal dispersion; L-AmB, liposomal amphotericin B.

Figure 2 Nanostructured drug delivery systems modified.

Notes: (A) Liposome. (B) Solid lipid nanporticles. (C) Polymeric nanoparticles. (D) Silica; magnetic nanoparticles. (E) Carbon nanoparticles.

Table 1 Effect of AmB formulations ABLC and ABCD with different fungal species

Disease/microorganism	Treatment systems	Delivery properties	Pharmacokinetic	Category	References
Different fungal species, including Paracoccidioides brasiliensis	AmB	ABCD	Not reported	In vitro	^Citation51
Fungal sinusitis Aspergillus quadrilineatus	AmB	ABCD	Initial dose of 0.5 mg/kg/10 d Increased gradually by 0.5 mg/kg every 3 days until a maximal dose of 2.5 mg/kg	Case study	^Citation47
Disseminated cryptococcosis	AmB	ABCD versus D-AmB	0.8 mg/kg	Murine	^Citation57
Mucormycosis	AmB	ABCD	Not reported	Case study	^Citation58
Liver transplant recipient	AmB	ABCD + ITZ	Not reported	Case study	^Citation59
Phaeohyphomycosis	ITZ	ABCD + ITZ	Not reported	Case study	^Citation59
Bone marrow transplant patients with invasive fungal infections	AmB	ABCD	7.5 mg/kg	Human	^Citation60
Lung transplant recipient with Fusarium solani infection	AmB	ABLC	5 mg/kg/d	Case study	^Citation44
Immunocompromised patients with candidemia	AmB	ABCD	3.9 mg/kg	Human	^Citation61
Meningitis by Cryptococcus neoformans	AmB Flucytosine Fluconazole	ABCD	5.0–7.5 mg/kg combined with flucytosine at 20–60 mg/kg/d and fluconazole at 30–40 mg/kg/d	Murine	^Citation48
Rhinocerebral mucormycosis	AmB	ABCD	5 mg/kg/d 4 mg/kg/d 6 mg/kg/d	Case study	^Citation62
Mucormycosis Candida dubliniensis	AmB AmB	ABLC ABLC ABCD L-AmB	5 mg/kg/d Not reported Not reported Not reported	Case study In vitro In vitro In vitro	63 45 45 45
Mucormycosis	AmB	ABCD	4.8 mg/kg	Human	^Citation60
Invasive aspergillosis	AmB	ABCD	6 mg/kg/d	Human	^Citation64
Aspergillus fumigatus	AmB	ABLC	5 mg/kg once daily ×4 days	Rats	^Citation46
Lung transplant recipients with invasive aspergillosis	AmB	ABLC	Not reported	Prophylactic use	^Citation54
Coccidioidal meningitis by Coccidioides immitis	AmB	ABLC versus D-AmB	D-AmB 1 mg/kg ABLC 7.5 mg/kg or 15 mg/kg	Rabbit	^Citation65
Cholestatic liver disease and fungal infection	AmB	ABCD	4 mg/kg	Case study	^Citation66
Acute myeloblastic leukemia and Rhizopus oryzae infection	AmB	ABCD	1×400 mg/d	Case study	^Citation49
Liver transplant recipients with invasive fungal infections	AmB	ABCD	Not reported	Prophylactic use	^Citation67

Abbreviations: AmB, amphotericin B; ABLC, amphotericin B lipid complex; ABCD, amphotericin B colloidal dispersion; D-AmB, AmB deoxycholate; ITZ, itraconazole; L-AmB, liposomal AmB.

Table 2 Liposomes in fungal diseases

Disease/microorganisms	Treatment	Category	References
Systemic candidiasis	L-AmB	Mouse	^Citation100
Hematologic malignancies	L-AmB	Human	^Citation93,Citation101
Hematologic malignancies and invasive sinonasal aspergillosis	L-AmB	Human	^Citation102
Candida albicans	L-AmB	In vitro	^Citation88
Inhibition of HIV replication	L-AmB	Human	^Citation103
Heart transplant and transplant pulmonary	L-AmB	Human	^Citation104
Aspergillosis liver transplant	L-AmB	Human	^Citation105,Citation106
Lymphoblastic leukemia and fusariosis	L-AmB	Human	^Citation107
Rhinocerebral and rhino-orbital mucormycosis	L-AmB	Human	^Citation108^–^Citation110
	L-AmB + micafungin
Cryptococcus neoformans	Aerosolized L-AmB	Mouse	^Citation89
Transplant recipients	L-AmB (AmBisome)	Human	^Citation105
Liver transplant and Rhizopus sinusitis	L-AmB	Human	^Citation111
Blastomycosis	L-AmB	Murine	^Citation80
AIDS and cryptococcosis	L-AmB	Human	^Citation112
C. albicans	Aerosolized L-AmB	Mouse	^Citation98
Cardiac mycetomas	L-AmB + fluconazole	Human	^Citation113
Invasive candidiasis	L-AmB + caspofungin	Murine	^Citation114
Catheter antifungal lock	L-AmB	Human	^Citation115
Exophiala dermatitidis	L-AmB	Murine	^Citation116
Fusarium verticillioides	L-AmB + terbinafine	Murine	^Citation117
C. albicans biofilm	L-AmB	Rabbit	^Citation93
C. albicans biofilm		In vitro	^Citation94
C. albicans and bloodstream isolates biofilms		Human	^Citation95
Intraventricular cryptococcoma	L-AmB + voriconazole	Case study	^Citation118
Kidney transplant	L-AmB	Case study	^Citation119
Esophageal histoplasmosis	Itraconazole
Cerebral aspergillosis by Aspergillus fumigatus	L-AmB	Case study	^Citation120
Invasive pulmonary aspergillosis	Nebulized L-AmB	Prophylaxis	^Citation92
Kidney transplant and mucormycosis (Rhizopus microsporus)	L-AmB + posaconazole	Case study	^Citation121
Leukemia and pulmonary mucormycoses	L-AmB		^Citation122
Hematologic malignancies and IFIs	L-AmB	Prophylaxis	^Citation123
Liver transplant and IFIs	L-AmB	Prophylaxis	^Citation106
Vertebral infection by C. albicans	L-AmB + flucytosine	Case study	^Citation124
Disseminated aspergillosis	L-AmB + erythropoietin	Mouse model	^Citation125
Invasive aspergillosis by A. fumigatus	L-AmB	Rabbit	^Citation82
Pulmonary aspergillosis	Nebulized L-AmB	Human	^Citation126^–^Citation128

Abbreviations: C. albicans, Candida albicans; L-AmB, liposomal amphotericin B; A. fumigatus, Aspergillus fumigates; IFI, invasive fungal infection.

Figure 3 Nanoparticles based on solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs).

Table 3 Antifungal drugs-loaded nanoparticles based on solid lipids (SLNs) and nanostructured lipid carriers (NLCs)

Disease/microorganism	Treatment	Delivery systems	Size	Category	References
Candidiasis	Miconazole nitrate (MN)	MN/SLN	206.39±9.37 nma	Rats	^Citation152
Cutaneous candidiasis	Fluconazole (FLZ)	SLN/FLZ NLC/FLZ	178 nm 134 nm	Rats Rats	153 153
Fungal vaginal C. albicans	Clotrimazole (CTZ) Miconazole	CTZ-NLC-gel Encapsulation of miconazole in the NLC	NA 200 nm	In vitro In vitro	154 155
Cutaneous candidiasis C. albicans	FLZ-loaded SLN SLNs of terbinafine hydrochloride (TH)	FLZ/SLN SLNs were incorporated into Carbopol gel	178.9±3.8 nma 300 nm	In vitro/in vivo In vivo	156 157
Vaginal infection –C. albicans	Ketoconazole (KTZ) and CTZ	SLNs based on polyoxyethylene-40 stearate (PEG-40 stearate) for the administration of such as KTZ and CTZ antifungal agents	NA	In vitro	^Citation158
Aspergillus flavus	Itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery	ITZ/SLNs stearic acid and palmitic acid	139–199 nm (stearic acid) 126–160 nm (palmitic acid)	In vitro	^Citation145
Pulmonary aspergillosis	Lipidic nanoparticles of amphotericin B were prepared by spray drying technique using hydroxypropylmethyl-cellulose (HPMC)	AmB/NLC spray drying	600–700 nm	In vivo	^Citation144

Note:

a Data shown as mean ± standard deviation.

Abbreviations: AmB, amphotericin B; C. albicans, Candida albicans; NA, not available.

Table 4 Polymeric and other nanoparticles with antifungal activity

Disease/microorganism	Treatment	Delivery systems/methods/size	Category	References
C. albicans	AmB, 5-fluorocytosine or rapamycin	Encapsulated in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy poly(ethylene glycol) (PEG-DSPE) micelles	In vitro	^Citation179
C. albicans	AmB	Poly(2-ethyl-2-oxazoline)-block-poly(aspartic acid) (PEOz-b-PAsp)/micelles	In vitro	^Citation180
Paracoccidioides	Peptide	Poly(lactic acid-glycolic acid) (PLGA)	In vitro	^Citation181
Cryptococcal meningitis	P10 (PLGA) nanoparticles	Amphotericin B (AmB)-polybutylcyanoacrylate nanoparticles (AmB-PBCA-NPs) modified with polysorbate 80: 69.0±28.6 nm	Mice	^Citation182
A. flavus	ITZ and coumarin	ITZ and coumarin-6 loaded polylactic-co-glycolic acid-nanoparticles (PLGA-ITZ) and PLGA-C6-NPs): 232 nm, 630 nm and 1,060 nm	In vitro	^Citation183
P. brasiliensis	ITZ	PLGA-dimercaptosuccinic acid (DMSA) nanoparticles: 174±86 nm	In vitro	^Citation184
A. niger and Fusarium oxysporum	Not applicable	Surface-modified sulfur nanoparticles (SNPs)/polyethylene glycol-400 (PEG-400)	In vitro	^Citation185
C. albicans	AmB	Poly(epsilon-caprolactone) (PCL) and poly(N,N-dimethylamino-2-ethyl methacrylate) (PDMAEMA), or methoxy polyethylene glycol (PEG)	In vitro	^Citation186
C. albicans biofilm	Not applicable	Silicone catheter, polyvinyl chloride (PVC), and glass coated with titanium dioxide (TiO2) nanoparticles: 70–100 nm^2	In vitro	^Citation187
C. neoformans – meningoencephalitis	AmB	Angiopep-PEG-PE/AmB polymeric micelles	Murine	^Citation188
C. albicans, A. fumigatus, and Trichophyton rubrum	AmB	Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions	Mouse	^Citation189
Corneal fungal infections (Flu-CNGs)	FLZ	FLZ-loaded chitin nanogels	In vitro	^Citation190
A. flavus and Aspergillus terreus	Silver nanoparticles	Silver nanoparticle-encapsulated functionalized chitosan was prepared by the phase transfer method	In vitro	^Citation191
C. albicans and C. glabrata	CTZ	CTZ-loaded cationic nanocapsules using Eudragit^® RS100: 144 nm	In vitro	^Citation192
C. albicans	CTZ	CLZ-loaded nanovesicular carriers (ocular nanovesicular carrier)	In vitro	^Citation193
C. albicans and C. glabrata biofilm	Silver nanoparticles	Not applicable	In vitro	^Citation176
C. albicans and C. glabrata	CTZ	Coconut oil-core nanocapsules prepared from Eudragit^® RS100: 200 nm	In vitro	^Citation194
C. albicans	Not applicable	Polyethyleneimine (PEI) and PEI-based nanoparticles (nano-PEI)	In vitro	^Citation195
C. albicans biofilm	Silver nanoparticles	Not applicable	In vitro	^Citation177

Abbreviations: C. albicans, Candida albicans; AmB, amphotericin B; ITZ, Itraconazole; A. flavus, Aspergillus flavus; P. brasiliensis, Paracoccidiodes brasiliensis; A. niger, Aspergillus niger; C. neoformans, Cryptococcus neoformans; CTZ, Clotrimazole; C. glabrata, Candida glabrata.

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