Nanomedicine as an emerging approach against intracellular pathogens

Figures & data

Table 1 Summary of disease-causing intracellular pathogens

	Associated disease(s)	References
Viral pathogens
Herpes simplex	Type 1: oral herpes (cold sore, fever blister) or Type 2: genital herpes (warts, ulcers)	^Citation1,Citation2
Hepatitis C	Liver cirrhosis, hepatocellular carcinoma (HCC)	^Citation3,Citation4
Respiratory syncytial virus	Pediatric viral respiratory disease	^Citation5,Citation6
Human immunodeficiency virus	Acquired immunodeficiency syndrome (AIDS)	^Citation7,Citation8
Bacterial pathogens
Mycobacterium tuberculosis	Tuberculosis	^Citation9,Citation10
Salmonella enterica serovars Typhi, Paratyphi	Typhoid fever	^Citation11,Citation12
Brucella species B. melitensis, B. abortus, B. suis	Malta fever or undulant fever	^Citation13–Citation15
Listeria monocytogenes	Listeriosis, meningitis in newborn babies	^Citation16
Fungal pathogens
Candidia albicans	Multiple cutaneous and mucosal forms; frequently encountered oral form is thrush	^Citation17
Aspergillus fumigatus	Pulmonary aspergillosis	^Citation18
Other pathogens
Leishmania (parasite)	Cutaneous or tegumentary leishmaniasis	^Citation19,Citation20
Plasmodium species (protist) P. vivax, P. ovale, P. malariae, P. falciparum, P. knowlesi.	Malaria	^Citation21

Table 2A Current therapeutic strategies against selected viral pathogens

Virus name	Type of virus	Current treatment options	Drugs commonly prescribed	Drug class/mode of action	References
Human immunodeficiency virus (HIV)	Retrovirus (lentivirus)	Highly active anti-retroviral therapy (HAART; combination therapy using three or more antivirals simutaneously). Drugs may be administered individually or as combination pills.a Treatment duration is often lifetime of the patient.	Nevirapine, delavirdine, efavirenz, etravirine	Non-nucleoside reverse transcriptase inhibitor (NNRTI)	^Citation8,Citation42–Citation45
			Tenofovir disoproxil fumarate (TDF), azidothymidine, abacavir, lamivudine, zalcitabine, didanosine, stavudine	Nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)
			Atazanavir, darunavir, fosamprenavir, lopinavir, tipranavir, indinavir, emtricitabine, saquinavir, lopinavir, ritonavir, nelfinavir	Protease inhibitor (PI)
			Enfuvirtide	Entry/fusion inhibitor (FI)
			Maraviroc	CCR5 antagonist
			Raltegravir	Integrase inhibitor
Hepatitis C virus (HCV)	RNA virus (single strand, positive sense)	Combination treatment with interferon and broad-spectrumb antiviral drugs. Treatment duration is several months.	Pegylated interferon 2-alpha and ribavirin	PEG-IFN is an immunomodulatory drug and helps enhance natural anti-viral mechanisms (degradation of viral RNA, translation inhibition, etc) although the exact mechanism is unkown.	^Citation4,Citation47,Citation48
				Ribavirin is a purine analog and is incorporated into the genome of the virus, causing lethal mutations. It is ineffective against HCV when administered alone; it must be administered concomitantly with PEG-IFN.
Respiratory syncytial virus (RSV)	RNA virus (single strand, negative sense)	Prophylatic administration of antibodies as disease prevention, or disease treatment with broadspectrum antiviral drugs.c	Ribavirin or palivizumab	Ribavirin is a broad-spectrum antiviral drug that has shown some clinical benefit in RSV infections. It is the only FDA-approved drug for RSV treatment.	^Citation5,Citation6
				Palivizumab is a monoclonal anti-RSV antibody (mAb). It targets the RSV F glycoprotein, inhibiting viral entry into host cells. Recommended for RSV prevention rather than treatment.
Herpes simplex virus (HSV)	DNA virus (double stranded)	Antiviral drug administration until symptoms and viral shedding are reduced. Suppressive therapy is often recommended.	Acyclovir, valacyclovir, famciclovir, ganciclovir	Guanosine analog; these are potent inhibitors of the viral DNA polymerase. Requires phosphorylation by viral thymidine kinase.	^Citation1,Citation2
			Cidofovir	Competitive inhibitor of viral DNA polymerase; reserved for cases of acyclovir resistance due to high toxicity.
			Foscarnet	Pyrophosphate; inhibits viral DNA polymerase without requiring phosphorylation by viral kinases.

a Notes: Examples of combination pills include: Combivir, Kaletra, Truvada, Trizivir, Atripla, Epizicom/Kivexa (all registered trademarks of their respective companies);

b HCV-specific antivirals are currently under development in clinical trials. None have been FDA-approved to date;

c there are multiple RSV-targeted therapies currently under development, including: improved mAb preparations (motavizumab), antisense anti-RSV siRNAs, fusion inhibitors and other small molecule RSV viral epitope inhibitors. A variety of vaccine options are being explored as well (live, attenuated vaccines, vector vaccines and subunit vaccines).

Figure 1 Potential locations of intracellular pathogens. In a typical eukaryotic cell, pathogens may be internalized via endocytic mechanisms before establishing their intracellular life cycle. Pathogens may reside in various locations, including the cytosol, phagosome, lysosome, or vacuole compartments and the nucleus, and some may associate with the Golgi apparatus or endoplasmic reticulum. (1) Cytosol (Francisella tularensis,⁵⁷ Listeria monocytogenes,⁵⁸ Shigella⁶⁴). (2) Phagosome/lysosome or vacuole (Mycobacterium tuberculosis,^43,45 Brucella species,¹⁵ Salmonella,^52,53 Legionella⁵⁶). (3) Nucleus (herpes simplex virus,^1,60 HIV⁵⁹). (4) Golgi apparatus (Chlamydia⁶¹). (5) Endoplasmic reticulum (hepatitis C virus,⁶⁵ Brucella,⁶³ Toxoplasma gondii,⁶⁶ Legionella pneumophilia^62,64).

Note: Reproduced with permission from the Scripps Institution of Oceanography, UCSD.

Abbreviations: HIV, human immunodeficiency virus; UCSD, University of California, San Diego.

Table 2B Current therapeutic strategies against common intracellular bacterial pathogens

Bacteria	Associated disease(s)	Current treatment options	Drugs commonly prescribed	Drug class/mode of action	References
Mycobacterium tuberculosis	Tuberculosis	Long-term antibiotic treatment in two phases: intensive 2-month initial phase (four first-line drugs) then 4-month follow up (isoniazid and rifampicin only). Drug resistant strains require additional treatment for up to 12 months.	Isoniazid, pyrazinamide, rifampicin, ethambutol	First-line drugs effective against non-resistant M. tuberculosis infections. (non-MDR-TB)	^Citation30,Citation31,Citation34,Citation37,Citation38
			Ethionamide, prothionamide, cycloserine, capreomycin, paraaminosalicylic acid, fluoroquinolones	Second-line drugs effective against multi-drug resistant strains of M. tuberculosis. (MDR-TB)
Salmonella enterica (Serovars Typhi, Paratyphi)	Typhoid fever	Best therapy is prevention through vaccination. Chloramphenicol is a first-line drug of choice, although there is increasing bacterial resistance to this drug. Other recommendations include treatment with cephalosporins, fluoroquinolones or azithromycin in the case of highly drug resistant strains of Salmonella.	Chloramphenicol	Broad-spectrum protein synthesis inhibitor; emerging bacterial resistance to this antibiotic	^Citation50,Citation51,Citation52,Citation54,Citation55
			Ciprofloxacin	Fluoroquinolones (inhibit bacterial DNA replication)
			Ceftriaxone, cefotaxime	Cephalosporins (inhibit cell wall synthesis; a type of beta-lactam antibiotic)
			Azithromycin	Macrolide antibiotic (inhibits bacterial protein synthesis)
Brucella (melitensis, abortus, suis, canis)	Brucellosis, malta fever	Long-term antibiotic treatment; combination therapy more effective than monotherapy.	Doxycycline with streptomycin, gentamicin or rifampicin	Tetracycline-aminoglycoside combination (protein synthesis inhibitors)	^Citation13,Citation14,Citation15

Table 3 Examples of biocompatible nanoparticles discussed in this review

Type of nanoparticle	Materials used	References
Synthetic or man-made polymers	Poly (lactide-co-glycolide) (PLGA)	^Citation76–Citation81
	Poly-lactic acid (PLA)	^Citation77,Citation82,Citation83
	Polymethacrylic acid (PMA)	^Citation84,Citation85
	Polyethylene glycol (PEG)	^Citation77,Citation86,Citation87
Natural polymers	Chitosan	^Citation88,Citation89
	Gelatin	^Citation90,Citation91
	Alginate	^Citation92,Citation93
Other types	Lipids of nanoparticles	^Citation94–Citation96
	Gold	^Citation75,Citation97
	Silica-based compounds	^Citation98–Citation101

Figure 2 Components of an “ideal” nanoparticle for intracellular drug delivery. The important components of a nanoparticle used for intracellular drug delivery include choice of nanomaterials (eg, polymer, gold), targeting molecules, cellpenetrating peptides (to promote internalization), and the incorporated drug molecules of interest.

Abbreviation: PEG, polyethylene glycol.

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