Nanomedicine and cancer immunotherapy: focus on indoleamine 2,3-dioxygenase inhibitors

Figures & data

Table 1 Nanotechnological carrier systems used for cancer treatments

Indication	Nanotechnological system	Compounds (agents)	Status
Leukemia	Liposome	Topotecan + amlodipine^Citation121 6-Mercaptopurine + daunorubicin^Citation122	Preclinical
	Transferrin-conjugated PEGylated liposome Folate-G5 poly-propyleneimine dendrimer with ethylenediamine core	Doxorubicin + verapamil^Citation123 Methotrexate + all-trans-retinoic acid^Citation124
Breast cancer	Liposome	Gemcitabine + tamoxifen^Citation125 Ceramide + sorafenib^Citation126
	HER2 conjugated-GMO-MNPs	Paclitaxel + rapamycin^Citation127
Prostate cancer	HPMA-Gem-Dox Aptamer-G4 PAMAM dendrimer conjugates	Gemcitabine + doxorubicin^Citation128 Unmethylated CpG-ONTs + doxorubicin^Citation129
Glioblastoma	G5 PAMAM dendrimer RGDfK-G3 poly-lysine dendrimer	Antisense-miRNA21 + 5-fluorouracil^Citation130 Doxorubicin + siRNA^Citation131
Cervical cancer	Liposome	PD0325901 + siMcl1^Citation132
Lung cancer	Liposome	Doxorubicin + msurvivin T34A plasmid^Citation133
Brain cancer	PEG-liposome	Topotecan + vincristine^Citation134
Hepatocellular carcinoma	PLGA	Vincristine + verapamil^Citation135
Advanced colorectal cancer	Liposome (CPX-1)	Irinotecan + floxuridine^Citation136	Phase II
	Liposome (CPX-351)	Cytarabine + daunorubicin^Citation137

Abbreviations: GMO, glycerol monooleate; HER2, human epidermal growth factor receptor 2; HPMA, N-(2-hydroxypropyl)methacrylamide; miRNA, microRNA; MNPs, magnetic nanoparticles; ONTs, oligonucleotides; PAMAM, polyamidoamine; PEG, polyethylene glycol; PLGA, poly lactic-co-glycolic acid; siRNA, small interfering RNA.

Table 2 US FDA approved nanomedicines used for cancer treatments

Drug	Class	Platform	Drug carried ratio	Diameter (mm)	Dose (mg^2/m)	References
Doxorubicin	Liposome	Doxil^®	10,000–15,000	100	25–80	Gabizon et al^Citation16 and Hamilton et al^Citation138
Vincristine	Liposome	Marqibo	~10,000	100	2.0–2.25	Bedikian et al^Citation139 and Silverman and Deitcher^Citation140
Daunorubicin	Liposome	Daunoxome	~10,000	50	10–190	Gill et al^Citation141 and Bellott et al^Citation142
Mertansine	Antibody–drug conjugates	Trastuzumab emtansine	≤8	~10	10–160	Lu et al^Citation143
Monomethyl auristan E	Antibody–drug conjugates	Brentuximab vedotin	≤8	~10	90–110	Younes et al^Citation144 and Bradley et al^Citation145
Paclitaxel	Protein carrier	Abraxane^®	>10,000	130	150–300	Ando et al^Citation146

Abbreviation: FDA, Food and Drug Administration.

Figure 1 IDO pathway and inhibitors.

Notes: Tryptophan catabolism through the kynurenine pathway involves IDO an intracellular rate limiting enzyme and possible natural and synthetic inhibitors of this enzyme acting through various routes. IDO serves as an apoenzyme which is encoded by the Indo gene, this gene is upregulated by JAK/STAT signaling pathway induced by IFN-γ, cyclooxygenase-mediating prostaglandin E2, TNF-α and LPS regulated by NF-κB. In contrast, it is downregulated by BIN gene, IL-4, nitric oxide and TGF-β through mRNA degradation pathway. Apart from the natural and synthetic inhibitors certain tryptophan active products, such as tryptamine and DMT, also serve as modulators of this enzyme.
Abbreviations: COX-2, cyclooxygenase-2; DMT, N-dimethyltryptamine; IDO, indoleamine 2,3-dioxygenase; IFN- γ, interferon gamma; IL, interleukin; JAK, Janus kinase; LPS, lipopolysaccharides; mRNA, messenger RNA; NAD, aldehyde dehydrogenase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; PG, prostaglandin; PGE2, prostaglandin E2; STAT, signal transducers and activators of transcription; TGF- β, transforming growth factor β; TNF, tumor necrosis factor; T-reg, T-regulatory cells.

Figure 2 Natural inhibitors with structures.

Notes: (A) Brassinin,⁷⁶ (B) annulin A,⁷⁸ (C) annulin B,⁷⁸ (D) adociaquinone A,⁷² (E) adociaquinone B,⁷² (F) exiguamine A,⁷⁵ (G) tryptamine,⁷⁹ (H) curcumin,⁸³ (I) epigallocatechin gallate,⁸⁰ (J) tryptanthrin,⁸⁵ (K) 3,3′-diindolylmethane,⁷⁵ (L) p-coumaric acid,⁸⁸ and (M) thielavin.⁵⁹

Table 3 Physicochemical properties of selected natural inhibitors

Natural inhibitor	Molecular weight (Da)	Polar surface area (Å^2)	Molecular surface area (Å^2)	Partition coefficient (log P)
Brassinin	236.35	27.82	310.98	3.28
Annulin A	360.35	110.13	501.95	3.20
Annulin B	386.39	106.97	547.34	4.13
Adociaquinone A	520.77	110.52	423.438	1.10
Adociaquinone B	423.43	110.52	520.92	1.10
Exiguamine A	492.50	146.03	647.56	−1.85
Tryptamine	160.21	41.81	252.62	1.49
Curcumin	368.37	93.06	509.73	4.12
Epigallocatechin gallate	458.37	197.37	556.67	3.08
Tryptanthrin	248.23	49.74	299.16	2.40
3,3′-Diindolylmethane	246.30	31.58	352.74	4.26
p-Coumaric acid	164.15	57.53	216.51	1.83
Thielavin	580.62	148.82	869.53	9.30

Note: Physicochemical properties of selected natural inhibitors retrieved from Watkins et al.¹⁴⁷

Figure 3 Synthetic inhibitors with structures.

Notes: (A) Norhaman,⁹⁶ (B) 4-phenylimidazole,⁹⁷ (C) 5-bromo-brassinin,¹⁰² (D) nitric oxide,¹⁰⁴ (E) 1-methyl tryptophan,⁶² (F) 2-mercaptobenzothiazole,¹⁰⁸ (G) 2-mercapto-4-phenylthiazole,¹⁰⁸ (H) methyl-thiohydantoin-L-tryptophan,¹⁰⁸ (I) phenformin,⁷³ (J) phenylthiazole,¹⁰⁸ and (K) cinnabarinic acid.⁹⁵

Table 4 Physicochemical properties of selected synthetic inhibitors

Synthetic inhibitors	Molecular weight (Da)	Polar surface area (Å^2)	Molecular surface area (Å^2)	Partition coefficient (log P)
Norharman (9H-pyrido [3,4-b]indole)	168.19	28.68	230.63	1.87
4-Phenylimidazole	144.17	28.68	211.56	1.89
Salicylic acid	138.12	57.53	183.54	1.98
Ascorbic acid	176.12	107.22	208.27	−1.91
Nitric oxide	30.00	34.14	48.22	−0.35
1-Methyl tryptophan	218.25	68.11	322.23	1.32
2-Mercapto-benzothiazole	167.25	12.89	191.43	2.89
2-Mercapto-4-phenylthiazole	193.28	12.89	236.29	3.44
Phenylthiazole	161.22	12.89	215.12	2.66
Imidodicarbonimidic diamide	101.11	111.77	130.40	−1.46
4-Amino-1,2,5-oxadiazole-3-carboximidamide	127.10	114.81	147.82	−1.37
Phenformin	205.25	102.78	302.68	0.34
Cinnabarinic acid	300.22	139.28	311.10	0.44

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