Nanotechnology for Diagnosis and Treatment of Infectious Diseases

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ReviewJournal of

Nanoscience and NanotechnologyVol. 14, 7374–7387, 2014

www.aspbs.com/jnn

Nanotechnology for Diagnosis and Treatment of

Infectious Diseases

Muhammad Qasim1, Dong-Jin Lim2, Hansoo Park1�∗, and Dokyun Na1�∗1School of Integrative Engineering, Chung-Ang University, Seoul, 156-756, Korea

2Department of Biomedical Engineering, University of Alabama at Birmingham, AL, 35233, USA

The emergence of co-infections and the evolution of drug-resistant pathogens limit the utility ofcurrent therapies against infections, and developing countries in particular are facing a great chal-lenge in combating infectious disease. Moreover, any failure to control the spread of infectiousdiseases would also represent a threat to developed countries. Recent developments in nanotech-nology allow us to address this issue at two levels: diagnostics and treatment. Prevention of thespread of infectious pathogens requires rapid and accurate identification of the infectious agentsfor proper treatment. Recently developed fluorescent nanoparticles are so sensitive that even asingle nanoparticle is capable of emitting a strong enough signal to be captured, thus enablingearly identification of infections. Proper and effective treatment not only saves the patient, but alsoprevents the spread of the pathogens. Specific nanoparticle vehicles developed to encapsulate ther-apeutic agents and deliver them to a target site represent a promising strategy to boost immuneresponses for vaccination and boost the efficacy of drugs for treatment. Here, we describe a varietyof nanotechnologies for use in applications such as immune response modulation, drug delivery,diagnostics, and treatment, which are especially needed in developing countries.

Keywords: Infectious Diseases, Nanotechnology, Drug Resistance, Therapies, Diagnostics.

CONTENTS1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7374

1.1. The Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7376

1.2. Current Treatments and Their Limitations . . . . . . . . . . . . . 7376

1.3. Current Diagnostic Techniques and

Their Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7378

2. Nanotechnology and Infectious Disease . . . . . . . . . . . . . . . . . . . 7379

2.1. Modulation of Immune Response by Nanoparticles

(NPs) for Efficient Vaccination . . . . . . . . . . . . . . . . . . . . . 7379

2.2. Nano-Based Drug Delivery System for

Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7380

2.3. Nanoparticles as Therapeutic Drugs . . . . . . . . . . . . . . . . . . 7382

2.4. Nano-Based Diagnosis of Infectious Diseases . . . . . . . . . . 7383

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7384

Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7385

References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7385

1. INTRODUCTIONPathogens such as viruses,1–4 bacteria,5�6 fungi,7 or

parasites8 that cause infectious diseases are one of the

major causes of deaths, accounting for approximately

∗Authors to whom correspondence should be addressed.

15 million annual deaths worldwide.9�10 Of the many

infectious diseases, acute respiratory infections including

influenza and pneumonia are the top-ranked causes of

deaths, accounting for 3.5 million deaths a year, followed

by acquired immunodeficiency syndrome (AIDS), which

is responsible for 2.5 million deaths. Other infectious dis-

eases such as diarrheal diseases, pneumonia, tuberculosis

(TB), and malaria are also major causes of deaths, account-

ing for 2.2 million, 1.8 million, 1.5 million, and 1.2 million

deaths, respectively.11�12 For example, in 2010, 8.8 million

people were infected with TB and 1.5 million of them died

of it. Over 95% of the deaths caused by infectious diseases

occur in low-income and mid-income countries.13

Despite great efforts to develop effective pharmaceuti-

cals and new technologies to produce drugs at low cost,

the remarkable increase in drug resistance of infectious

agents prevents efficient treatment of these diseases. The

discovery of penicillin was one of the greatest advances in

health care in the 20th century and antibiotics have dramat-

ically increased the survival rate for infectious diseases.

However, overuse or misuse of antibiotics or incomplete

therapy may result in the emergence of resistant infectious

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Qasim et al. Nanotechnology for Diagnosis and Treatment of Infectious Diseases

bacteria. Bacteria can evolve to defend themselves against

antibiotics through genetic mutations or the acquisition

of antibiotic-resistant genes. Methicillin-resistant Staphy-lococcus aureus and vancomycin-resistant Enterococcusare well-known examples of drug-resistant bacteria that

have been reported to prolong the state of illness and

increase the death rate.14

Infections caused by drug-resistant microorganisms

often fail to respond to conventional treatment, result-

ing in prolonged infection and increased risk of death.

Muhammad Qasim has completed his M.Phil. degree form Quaid I Azam University

Islamabad Pakistan in the field of Molecular Biology and Biochemistry in 2011. He moved

to Graduate School of Integrative Engineering at Chung Ang University for his doctoral

degree. His research interests are biomaterials applications for infectious diseases treat-

ments and diagnostics, nano drug delivery systems and tissue engineering.

Dong-Jin Lim earned his bachelor’s of science degree in Chemical Engineering at

Hanyang University, where he also obtained his master’s degree in biochemical engineer-

ing. Following his initial academic stint, he gained thorough experience working in both

the cosmetic and industrial food processing fields. After gaining many years of industrial

experience, he earned his Ph.D. in Biomedical Engineering at the University of Alabama

at Birmingham. His research interests include stem cells and tissue engineering as well as

the fabrication of microfluidic devices.

Hansoo Park is an assistant professor in School of Integrative Engineering in Chung-Ang

University. He has an undergraduate degree in the Department of Chemical Engineering

at Hanyang University, a master degree in the Department of Chemical Engineering at

Korea Advanced Institute of Science and Technology, and a Ph.D. degree in the Depart-

ment of Bioengineering at Rice University. He joined Stanford University for a post-doc

researcher. His current research interests include biomaterials for stem cell engineering,

tissue engineering, drug delivery system, and cancer treatment.

Dokyun Na is an assistant professor in School of Integrative Engineering in Chung-Ang

University. He has an undergraduate degree in the Division of Life Science at Korea

University, a master degree in the Graduate School of Biotechnology at Korea Uni-

versity, and a Ph.D. degree in the Department of Bio and Brain Engineering at Korea

Advanced Institute of Science and Technology. He has worked at the University of British

Columbia (Canada) as a research associate before joining Chung-Ang University. He

has very diverse research interests including synthetic biology to create novel regulatory

RNAs, systems biology to unveil the disease progression mechanisms of brain diseases,

computational biology to model cellular networks, metabolic engineering to construct sus-

tainable biofactories, bioinformatics to investigate the functions of unstructured proteins,

and nanobiotechnology to develop microfluidic devices for drug discovery.

In addition, patients infected with such microorganisms

remain infectious for a long time, increasing the risk of

spreading the disease to others.

At the present time approximately 70% of the infectious

bacteria found in hospitals are resistant to at least one of

the antibiotic agents commonly used for treatment. The

World Health Organization (WHO) reported approximately

400,000 multidrug-resistant TB (MDR-TB) cases through-

out the world in 2011. MDR-TB is caused by a form of

mutated bacteria that has evolved to survive treatment with

J. Nanosci. Nanotechnol. 14, 7374–7387, 2014 7375



Nanotechnology for Diagnosis and Treatment of Infectious Diseases Qasim et al.

at least two of the primary antibiotic drugs.15�16 The conse-

quences of antimicrobial resistance were higher mortality,

increased cost due to the use of more expensive drugs, and

increased burden on the public health care system.

Consequently, there is an increase in the demand for

new strategies, pharmaceuticals, and devices to diag-

nose and treat diseases accurately, easily, and efficiently.

A number of nanotechnology-based materials have been

studied with the aim of effective control and prevention of

infectious diseases.17 Recently, nanotechnology has been

employed to enhance immune responses against antigens

for effective vaccination, to deliver pharmaceuticals to a

target site and release them at a controlled rate, and to

detect and identify diseases accurately and rapidly at low

cost. This review will discuss how nanotechnology has

improved the treatment, diagnostics, and prevention of

infectious diseases.

1.1. The Immune SystemHumans defend themselves from infection with for-

eign pathogens through the innate and adaptive immune

systems.17�18 The innate immune system acts as the first

line of defense against invading particles and consists

of several cell types including dendritic cells (DCs),

macrophages, and natural killer (NK) cells, whose primary

role is to eliminate foreign materials without specificity.19

The innate immune cells often recognize common fea-

tures of pathogens such as lipopolysaccharides for effi-

cient defense. Antigen-presenting cells (APCs), including

DCs, are able to digest foreign materials into fragments

and present these fragments on their membrane surface

through major histocompatibility complex (MHC) class

II proteins. The presented antigens trigger the adaptive

immune system, which acts as a second line of defense

and is composed of highly specialized processes that

eliminate infection through the antigen-specific responses

of humoral and cell-mediated immunity.20 This adap-

tive immunity displays antigenic specificity, diversity, and

memorization.

The role of humoral immunity is to eliminate foreign

antigens from the body. Once antigens are presented on

APCs, B cells that recognize the antigens are activated

to undergo clonal expansion and differentiate into plasma

cells, specialized factories that produce antibodies. Certain

activated B cells differentiate into memory cells, which are

able to rapidly differentiate into plasma cells. Upon second

infection the antigens are recognized and can be quickly

eliminated by the memory cells.

The role of cell-mediated immunity is to eliminate

virus-infected host cells. Every cell in our body presents

its own protein fragments on MHC class I molecules. Den-

dritic cells ingest viruses and present virus molecules on

their surface. Various subpopulations of cytotoxic T cells

recognize the presented virus antigens and become acti-

vated. When activated cytotoxic T cells recognize corre-

sponding antigens presented by MHC class I molecules of

infected host cells they send signals that trigger apoptosis

of the infected cells.

1.2. Current Treatments and Their LimitationsOver the centuries medical research has improved our

understanding of microorganisms and has accordingly led

to better prevention and treatment of infectious diseases

through the discovery of antibiotics, antitoxins, antivirals,

antifungals, and vaccines.21�22 Of these discoveries, the

invention of vaccines was a great leap forward in the man-

agement of infectious diseases because it prevented the

spread of disease rather than treating the disease after

infection. The success of vaccination is illustrated by the

elimination of small pox.23�24

Recently, several therapeutic strategies have been devel-

oped to treat bacterial and viral infections that were pre-

viously considered difficult to conquer. Nonetheless, it

can be hard to recover completely from infection and

there is a great demand for new technologies to diag-

nose, treat, and possibly prevent infection. Below, we dis-

cuss treatment strategies for three well-known infectious

agents: Mycobacterium tuberculosis, Human Immunodefi-

ciency virus (HIV), and Hepatitis C Virus (HCV).

TB is caused by the mycobacterium M. tuberculosistherefore antibiotics are commonly used for treatment.

There are two phases of antibiotic treatment for TB infec-

tion. The first phase is intensive treatment, which involves

a combination of the antibiotics isoniazid, ehtambutol,

rifampicin, and pyrazinamide. The second phase is a 4-

month treatment course with only rifampicin and isoniazid.

Complete eradication of TB requires both intensive and

continuous treatment for about 6 to 8 months. This is the

most effective treatment to date for TB, but because of the

long treatment period the drugs have side effects such as

jaundice, dyspepsia, exanthema, and arthralgia.25

For the treatment of acquired human deficiency syn-

drome (AIDS) caused by infection with HIV there are

currently five classes of drugs that inhibit the replication

and integration of the viral genome at different stages

in the life cycle of HIV-1 virus: nucleotide reverse tran-

scriptase inhibitors, non-nucleoside reverse transcriptase

inhibitors, protease inhibitors, fusion inhibitors, and inte-

grase inhibitors. At present these drugs are used in com-

bination and this regime is referred to as highly active

antiviral therapy (HAART). Most drugs used in HAART

are costly and have severe side effects, and furthermore

multi-drug resistance to these drugs has been reported.26

HCV is known as a silent killer of infected individu-

als because its symptoms only appear at a late stage of

infection. Chronic HCV infection can lead to liver cancer

and eventually death. Currently there are no available vac-

cines for HCV and therefore no way to prevent infection.

After infection, a combination of antiviral ribavirin and

interferon-� are used for treatment and complete removal

of virus from the bloodstream requires several months of

continuous therapy. However, these compounds are toxic

7376 J. Nanosci. Nanotechnol. 14, 7374–7387, 2014




Table I. Current therapies against selected pathogens and their limitations.

Current treatment

Disease name Causative agent strategies Commonly used drug agents Limitations in treatment Refs

Hepatitis C Hepatitis C (HCV) Combination of

interferon and

broad spectrum

anti-viral

therapy

Pegylated interferon-�, ribavirin,

and protease inhibitor.

—Limited efficacy in patients with

HCV genotype 1.

—Drug resistance is rapidly

emerging.

—Drug administration by injection

over 72 weeks may result in

chronic side effects

[1, 2]

Acquired

immunodeficiency

syndrome (AIDS)

Human

immunodeficiency

virus (HIV)

Highly active

antiretroviral

therapy

(HAART)

—Nucleoside reverse transcriptase

inhibitors (NRTIs): e.g.,

Lamivudine and Zidovudine

—Nonnucleoside reverse

transcriptase inhibitors (NNRTIs):

e.g., Rilpivirine

—Fusion inhibitors: e.g.,

Enfuvirtide

—Protease inhibitors: e.g.,

Tipranavir, Indinavir, and

Amprenavir

—Integrase inhibitors: e.g.,

Raltegravir and Dolutegravir

—Treatment should be continued

throughout life.

—Potential emergence of drug

resistance.

—Complete eradication is not

possible.

—Side effects such as increased

rate of heartbeat, diabetes, liver

diseases, cancer, and premature

aging.

[3]

Cervical cancer Human papilloma

virus (HPV)

Cryosurgery, loop

electrosurgical

excision

procedure

(LEEP), laser

therapy,

hysterectomy,

vaccine

Salicylic acid, aldara, zyclara,

condylox, trichloroacetic acid

—No treatment for existing cervical

cancer except for removal of

cervix.

—Vaccine has side effects and is

effective only before exposure to

the virus.

[35]

Hepatitis B Hepatitis B virus

(HBV)

Interferon therapy IFN-�, Pegylated interferon,

Lamivudine, Adefovir, Dipivoxil,

Entecavir, Telbivudine, and

Tenofovir

—No treatment available for acute

hepatitis B.

—Cold chain issues for vaccine.

—A booster dose of vaccine is

required therefore follow up of

patients is a major issue.

[4]

Malaria Plasmodium Combination

therapy of

antimalarial

drugs

Artemisinin, Prophylactic

Artemisinin

No vaccine available. [8]

Poliomyelitis Polio virus Vaccine No antiviral drugs available —No treatments available.

Immunization for prevention only.

—Vaccine is expensive and

requires a cold chain for

transportation and storage.

—Issue of oral polio vaccine

(OPV) degradation

[40, 41]

Influenza virus Influenza virus

A and B

Vaccine —Antiviral therapy and vaccination

—Adamantanes inhibitors

(Amantadine and Rimamtadine)

—Neuraminidase inhibitors

(Zanamivir and Oseltamivir)

—Vaccine for Influenza Virus A

(HIN1) Monovalent 2009 vaccine

—These drugs have activity only

against Influenza A strain.

—Amantadine carries a risk of

neuropsychological, atropinic and

dopaminergic adverse effects.

—Zanamivir carries a risk of

life-threatening bronchospasm.

—Emergence of drug resistance is

a crucial problem for treatment of

influenza virus.

[39]

Mumps, measles and

rubella

Paramyxo virus,

mumps virus

rubella

Vaccine MMR vaccine. —No treatment available. Vaccine

for prevention only

—Potential side effects of vaccine





Table I. Continued.

Current treatment

Disease name Causative agent strategies Commonly used drug agents Limitations in treatment Refs

Tuberculosis (TB) MycobacteriumTuberculosis

Antibiotics Isoniazide, Pyrazinamide,

Rifampicin, Ethambutol,

Ethionamide, Prothionamide,

Cycloserine, Capreomycin,

Paraaminosalicylic Acid,

Fluroroquinolones

—No vaccine available.

—Drug resistance may emerge due

to breakdown of therapy by

patients therefore TB is

re-emerging.

—Drug administration requires the

presence of a second person.

[37, 38]

Candidiasis Candida species Antifungal agents Fluconazole, Itraconazole,

Posaconazole, Clotrimazole,

Amphotericin B, Deoxycholate,

Econazole, Ciclopirox,

Miconazole, Ketoconazole,

Nystatin, Clotrimazole,

Voriconazole, Candins,

Flucytosine, Ravuconazole,

Posaconazole, Micafungin, and

Anidulafungin

—Most antifungal drugs have low

water solubility due to

hydrophobic nature.

—Drug resistance has emerged

against the two most useful

antifungal drugs, Amphotericin B

and Ketoconazole.

[7]

Leishmaniasis Leishmania species Antifungal and

Antileishmanial

drugs

Liposomal Amphotericin B,

Ketoconazole, Paromomycin

(Humatin) and Miltefosine

(Miltex).

Anti-leishmanial drugs are toxic and

have to be administered

parenterally for long periods,

especially for visceral

leishmaniasis.

—Re-emergence of diseases due to

drug resistance, especially in

tropical areas.

[36]

and have severe side effects, and moreover are not equally

effective for all genotypes of HCV.27

Despite the discovery and development of new thera-

peutic strategies for treatment, complete prevention and

eradication of infectious diseases has not been achieved.

Certain therapeutic compounds have serious side effects

and therefore cannot be widely applied; for example, nerve

damage caused by the DPT vaccine (diphtheria, pertussis,

and tetanus) and long-term pain, numbness, infertility, and

paralysis due to the HPV vaccine in Japan. Moreover, cer-

tain retroviruses change their genomic sequence at a high

rate therefore no effective vaccines have been developed.

Available strategies and therapeutics, as well as their lim-

itations, are listed in Table I.

In addition to the difficulty in developing new therapeu-

tics, emergence of drug resistance of existing pathogens

that escape from current treatment strategies is another

significant problem in infectious diseases. The world-

wide prevalence of drug-resistant strains indicates that

this is a global issue.5�28 The Center for Disease Con-

trol and Prevention reported that the number of annual

infections by multidrug-resistant Staphylococcus aureus(MRSA) increased from 127,000 in 1999 to 278,000 in

2005.16�29 Similarly, the number of annual deaths caused

by MRSA in the United States increased from 11,000 in

2005 to 17,000 in 2007.30 Recently, more than 1,500 peo-

ple in Germany were infected with a new virulent strain

of Escherichia coli (104:H4) that has not been reported in

any prior outbreaks.6

1.3. Current Diagnostic Techniques andTheir Limitations

Effective treatment and prevention of infectious diseases

requires up-to-date diagnostics. In addition, the efficacy of

treatment should be monitored during therapy by detec-

tion of pathogens. Conventional techniques available for

the diagnosis of infectious disease include microscopy,

tissue culture, lateral flow immunoassays (also known

as dipsticks or immune chromatographic test, ICTs),

enzyme-linked immunosorbent assays (ELISAs), and bio-

chemical tests (Table II). More recently, molecular diag-

nostics techniques such as polymerase chain reaction

(PCR) and real-time PCR have been widely used to diag-

nose and monitor infections such as HIV/AIDS and HCV

because they have a higher specificity and sensitivity than

ELISA-based diagnostics. However, because these tech-

niques are costly and time-consuming and require prior

sample preparation, they are commonly used in devel-

oped countries but are often poorly suited for developing

countries, where infectious diseases are leading causes of

morbidity and mortality, because the availability of trained

clinical staff and specific laboratory facilities may be

limited.31 Thus, there is a great demand for new diagnostic

technologies. The ideal diagnostic device for developing

countries would be a cost-effective, portable, and point-

of-source detection system that is also highly reliable,

sensitive, and accurate.32 Furthermore, the ideal diagnostic

technique would be able to detect multiple pathogens in a

single reaction.





Table II. Diagnostics tests for infectious diseases in developing countries and their limitations.42

Disease Diagnostic test Limitations

Acute respiratory

infections (ARIs)

Blood/sputum culture —Culture is time-consuming and costly and results are highly

dependent on stringent transport conditions to maintain specimen.

—Requires constant supply of reagents, well-maintained equipment,

and adequately trained staff.

Acquired

immunodeficiency

syndrome (AIDS)

—Serology (antigen/antibody detection); detection by

PCR amplification of the LTR region of gag gene,env gene, and pol gene

High rate of false negative and positives.

—PCR cannot be performed during the HIV incubation period.

—Nucleic acid amplification technologies (NAAT) such as PCR are

expensive and may produce many false positives due to

contamination

Diarrheal diseases —Microscopy stool culture Microscopy requires well-trained and supervised technologists.

—Pathogen culture is time-consuming and costly.

Malaria Blood film; antigen detection (dipstick); antibody

detection (ELISA and Rapid)

Rapid tests help to control disease spreading but have high false

positive rates.

Tuberculosis (TB) Sputum microscopy; pathogen solid and liquid culture;

Tuber skin test; PCR-based Gene Xpert

Microscopy requires experts and well-trained staff. Antibody tests,

Tuber skin test (tuberculin) may produce false positive result due

to allergic reactions.

Visceral leishmaniasis Direct agglutination test (DAT); serological field test;

microscopy/culture of spleen or bone morrow cells

Bone morrow sampling is painful and invasive.

Conventional molecular diagnostic technologies are

based on the amplification of specific DNA sequences

from extracted nucleic acids (DNA or RNA), for example

target amplification (e.g., PCR, reverse transcriptase

PCR (RT-PCR), and strand displacement amplification),

signal amplification (e.g., branched DNA assays and

hybrid capture), probe amplification (e.g., ligase chain

reaction, cleavage-invader, and cycling probes), or post-

amplification analysis (e.g., sequencing the amplified prod-

ucts or melting curve analysis). However, amplification

methods are so sensitive that false positives may easily

occur due to trace contamination of the specimen or equip-

ment. In addition, because these techniques depend on

enzymatic activity, false negatives can occur when samples

contain contaminants that inhibit the enzymes.33

DNA microarrays or DNA chips are one of the lat-

est methods for rapid infectious disease diagnostics. DNA

microarrays are essentially a high-throughput version of

the Southern blot method.34 Each microarray contains a

number of different DNA oligonucleotides that recognize

specific target genes from a pathogen through complemen-

tary DNA–DNA binding. Diagnosis is made by the detec-

tion of oligonucleotides hybridized to pathogen genes.

Although DNA microarrays have demonstrated poten-

tial in diagnostics their practical use in clinical settings is

hampered by several considerations, especially difficulties

in the identification of pathogen-unique target genes and in

the design of oligonucleotide primers for multiplex PCR.

The first difficulty lies in finding a gene that is unique

to a particular pathogen among a tremendous number

of genes.43 The gene most commonly used to identify

microorganisms is ribosomal 16S rRNA, because every

bacterium has a variant of the gene. However, organisms

belonging to the same species share a large number of

nucleotides in the 16S rDNA gene, which limits the identi-

fication of bacteria below the species level.44 Furthermore,

certain phylogenetically unrelated bacteria have been

reported to have very similar 16S rRNA sequences.

Another challenge is to design oligonucleotides that will

amplify particular pathogen genes in multiplex PCR with-

out non-specific amplifications. Because multiplex PCR is

limited to approximately a dozen reactions, several hundred

rounds of PCR would be required to completely cover all

the potential probes that identify all infectious diseases on

an array. PCR on such a massive scale is not practical in

routine use.

Emerging nanotechnology-based techniques have

recently attracted interest as an approach that may over-

come the problems of current diagnostic techniques

through their specific mode of actions and unique phys-

ical properties (i.e., shape, size, surface charge, and

dimension).45 These techniques may be applied to develop

accurate, reliable, rapid, safe, cost-efficient, sensitive,

specific, and easily accessible techniques for the detec-

tion of pathogens.46 In the following section we discuss

new nanotechnology-based methods for the treatment,

diagnosis, or prevention of infectious diseases.

2. NANOTECHNOLOGY ANDINFECTIOUS DISEASE

2.1. Modulation of Immune Response byNanoparticles (NPs) for Efficient Vaccination

Vaccines are specifically designed antigens that effectively

induce immune responses so that the immune system will

remember the antigens and can rapidly respond upon sub-

sequent infection. Vaccination is a reliable method of pre-

venting infectious diseases, and plays a very important

role in the control of mortalities and morbidities associated

with infectious diseases.47 It is estimated that vaccines pre-

vent almost 6 million deaths/year worldwide48 and a few

diseases such as smallpox have been successfully eradi-

cated through widespread vaccination programs.49





Effective vaccines must induce strong immune

responses. Conventional vaccines display various degrees

of immunogenicity and safety. For example, attenuated

vaccines are highly immunogenic but are also associated

with a risk of infection by the vaccines themselves as a

result of the virus reverting to a virulent form. On the

other hand, antigenic protein vaccines are not infectious

and therefore safer, but are less immunogenic and repeated

vaccination is required. Furthermore, a well-established

cold chain is required to transport vaccines safely and there

are insufficient facilities to store and transport vaccines in

developing countries. Recent advancements in nanotech-

nology have provided new approaches for effective immu-

nization against infectious diseases.

Activation of the cell-mediated immune response is an

important target to improve the efficacy of therapeutic

agents, especially vaccines.50 Nanoparticles (NPs) can be

used as a vessel to deliver encapsulated vaccines (anti-

genic proteins) to selective sites and release them over a

long period of time to boost the immune response (Fig. 1).

In addition, the NP formulation can be lyophilized into a

powder form, which prolongs shelf life of vaccines over

a wide range of temperatures (i.e., 0 �C to 40 �C).51 NPs

can therefore allow safe transportation of vaccines over a

long distance without the need for a cold chain.

Many NP systems have been employed for oral vac-

cines. Nanoscale aerosol vaccines have been developed for

respiratory pathogens including M. tuberculosis (MTB).

Edward et al. developed a micro- and nano-scale system

for aerosolized delivery of the attenuated MTB vaccine.22

The aerosol MTB vaccine showed a marked enhanced

immune response compared with the control MTB vaccine.

NPs can be utilized to facilitate antigen presentation

of APCs.53 NPs made up of pH-responsive polymers

help endosomal escape of the antigen into the cytosol.

Shen et al. demonstrated successful delivery of oval-

bumin protein encapsulated with poly lactic-co-glycolicacid (PLGA) NPs into mouse bone marrow-derived DCs,

and further reported that these DCs showed high and

Figure 1. Induction of immune responses by nanoparticle-based vaccine.

Notes: Use of NPs to induce immune responses for enhanced vaccination (adopted from [52], T. Akagi, et al., Polymer Nanomed. 247, 31 (2012).© 2012, Springer.)

sustained ovalbumin antigen presentation compared with

DCs stimulated with soluble ovalbumin antigens.54 NPs

have also been reported to enhance specific cellular and

humoral immune responses to the HIV-1 Tat protein.53�55�56

NPs with a positively charged surface can efficiently

absorb plasmid DNA. Intramuscular administration of NP-

encapsulated plasmids harboring the tat gene into mice

resulted in strong Tat-specific immune responses.56 Simi-

lar enhancement in the immune response to HIV has been

achieved by encapsulating the p24 subunit of HIV capsid

as the antigen with biodegradable poly lactic acid PLA

NPs.57

NPs can also function as adjuvants to enhance the

immunostimulatory properties of traditional vaccines.52

Adjuvants improve the immunogenicity of vaccines by

activating immune inflammatory reactions that further

induce memory responses. NPs can either carry adju-

vants or act as adjuvants themselves.58 MF59 is a nano-

sized oil-in-water emulsion (< 250 nm) developed from

squalene and two surfactants (polysorbate 80 and sor-

bitan tiroleate). These surfactants are used as an adju-

vant for influenza vaccine in many countries, and MF59

is currently the only vaccine adjuvant approved by the

FDA. MF59 provokes a strong humoral and cell-mediated

immune response compared with immunization with vac-

cine alone. MF59 has also been shown to significantly

enhance the immune response in HIV/AIDS treatment.59�60

A recent study showed that poly(lactic-co-glycolic acid)

(PLGA) NPs incorporating lipopolysaccharides (LPS) on

their surface induced the production of interleukin 1� (IL-

1�) in macrophages.61 Novel carbon NPs with a size of

470 nm showed significant success as an adjuvant for oral

vaccine delivery, because particles smaller than 1 �m will

favor uptake by microfold cells.55

2.2. Nano-Based Drug Delivery System forInfectious Diseases

Nano-scale drug delivery systems (nano-DDS) have the

following unique physical features: high solubility due





to their inherent hydrophilicity and solubilizing moieties,

thermo-sensitivity, and capability for controlled release of

encapsulated drugs, easy surface modification, and high

surface area-to-volume ratios. These unique features of

nano-DDS may allow medical scientists to overcome the

problems associated with the increased drug resistance of

infectious agents. By scaling down the size of compounds,

nano-DDS can modulate and improve the performance

of many drugs to an extent not achievable with conven-

tional drugs. Nano-DDS can encapsulate drugs and thereby

enhance their stability, solubility, and absorption. Nano-

DDS can also increase blood circulation time, deliver

drugs to specific cells or tissues, and release them in a

controlled manner in response to a specific stimulus.14

Targeted and efficient drug delivery becomes possible

with the use of NPs.62 NPs have the ability to encapsu-

late therapeutic agents or vaccines at high density. Because

these NPs protect encapsulated drugs from diffusion and

enzymatic degradation, the drugs can be delivered at high

doses to a particular target site.62 In addition, NPs are

able to release drugs at the slow rate required to prolong

immune responses.52 Importantly, certain NPs are able to

deliver drugs across the blood brain barrier (BBB), the

tight junction of endothelial cells that isolates and protects

the inner blood circulation of the brain from the rest of the

blood circulation.63�64 Thus, NPs are efficient drug delivery

vehicles for the treatment of diverse infectious diseases,

Figure 2. Various types of nanoparticles used in biomedical research and drug delivery.

Notes: This figure shows typical nano-based systems that can deliver encapsulated compounds to a target site.83

even those caused by viruses that form a reservoir in brain

blood lymphocytes such as HIV/AIDS.65

NPs have been developed using a variety of com-

ponents. NPs made of biodegradable and biocompati-

ble polymers have been developed for the delivery of

DNA vaccines.62 PLGA NPs encapsulating the HBV

surface antigen (HBsAg) gene enhanced the immune

response in mice.55 NPs made of polyactide-co-glycolids(PLG) have been used to encapsulate antigens in many

studies66 and NPs made of polyesters such as polylactide-

co-glycolides (PLG) and polylactic acids (PLA) have

been also used for antigen encapsulation and delivery.67

Nanoemulsions have been successfully used as a ves-

sel to deliver Hepatitis B antigens for needle-free nasal

immunization.68�69 NPs developed from smart materials

have the ability to respond to the surrounding environment

such as temperature or pH, and make it possible to con-

trol the release rate of encapsulated drugs at the target

site.70 There are many different nano-based drug deliv-

ery systems including nano-capsules,71 liposomes,72�73

dendrimers,74 nano-biomagnetic75–77 particles, attapulgite

clays with nano-pores,78 nano vaccines,49�79 quantum

dots,80 nanotubes,50 and nanogels81�82 (Fig. 2).

Typical nano-based drug delivery systems for infectious

diseases are described below. Nanogels form three-

dimensional cross-linking networks held together by phys-

ical or chemical bonds.84 Nanogels are hydrophilic and





therefore have the ability to absorb a large amount of water

while maintaining their structure and remaining undis-

solved. Smart nanogels with thermoresponsive properties

have been used to control drug release.82 Nanogels with

surface charge are able to enhance antifungal and antibac-

terial activity.85 Moreover, nanogels loaded with drugs can

be lyophilized into a powder form and can be transported

over long distances without a cold chain.86

Solid lipid NPs are stable and able to incorporate drugs

at high density, which reduces the risk of retention of

a high level of residual organic solvent.73 For example,

in the treatment of TB a single administration of solid

NPs encapsulating rifampicin, isoniazid, and pyrazinamide

was sufficient to elicit recovery from infection within

1 week, whereas non-encapsulated drugs must be admin-

istered every day for 1 week to obtain the same result.87

Liposomes are vesicular carriers of 20 to 30 nm in

size that are composed of phospholipid bilayers around

an aqueous core.88 Encapsulation and delivery of drugs

in liposomes has shown great success in the treatment of

HIV/AIDS. Encapsulation of Indinavir, an antiviral agent

used to treat HIV, in liposomes resulted in more effi-

cient delivery of the drug to lymphoid tissues than treat-

ment with soluble Indinavir and successfully reduced HIV

viral load and potentially recovered CD4 T cells.89 Load-

ing of Indinavir into lipid nano-capsules (LNCs) greatly

improved drug delivery to the brain and testis of mice.90

Similarly, when Zidovudine (AZT) was encapsulated in

liposomes, the accumulated concentration of AZT in lym-

phoid tissues was 27 times higher than when soluble AZT

was administered.91 The AZT plasma concentration was

also significantly higher in patients treated with AZT lipo-

somes compared with patients treated with AZT solution.92

Dendrimers are a hyper-branched and mono-dispersed

class of polymers with a defined molecular weight. They

have a central core and three-dimensional branches with

functionalized surface groups. Dendrimers improve the

solubility of hydrophobic drugs by ionic interactions and

thereby improve their efficacy.84 Targeting of the drug

efavirenz to monocytes/macrophages using a mannose-

targeting poly (propyleneimine) dendrimer increased the

cellular uptake of efavirenz up to 12-fold.93

A carbon nanotube is a tube-shaped material made of

carbon with a diameter in the nanometer scale. Carbon

nanotubes have diverse structural variations in thickness

and the number of layers of graphite. When nanotubes car-

rying siRNA specific for C-X-C chemokine receptor type

4 (CXCR4) were targeted to CD4 cells, the expression of

CXCR4 receptor proteins was reduced by 60–90%.50�74

2.3. Nanoparticles as Therapeutic DrugsNPs that have been developed to have novel immunother-

apeutic properties can themselves be used as drugs.94

Under UV light, metallic NPs and their oxides produce

reactive oxygen species that possess antimicrobial activity

Figure 3. Mechanisms by which nanoparticles kill bacteria cells.

Notes: Certain NPs and their ions produce free radicals that lead to oxida-

tive stress, for example through reactive oxygen species. These reactive

species induce damage in bacterial proteins and DNAs, which eventually

lead to bacterial death.

(Fig. 3).95 Metallic NPs incorporating Ag,96–98 Au,98�99

Cu,100 Ti,96 Mg, Zn,79 Fe, or metal oxides101 have signif-

icant antimicrobial, antifungal, and antiviral activities.102

Ag-NPs effectively kill many bacterial species including

E. coli, S. aureus, B. subtilis, and S. typhai.103 Cu-NPs canalso have a profound toxic effect; in one study no colonies

were formed when S. cerevisiae was incubated on a Cu-

NP-loaded polymer thin film.100

Nanomaterials with inherent antimicrobial activities are

called nanoantibiotics.102 Nitric oxide-releasing NPs (NO-

NPs) act through many simultaneous antimicrobial mecha-

nisms. NO exerts its antimicrobial activity largely through

reactive nitrogen oxide intermediates (RNOS), which are

formed after NO reacts with superoxide (O−2 ). The RNOS

react with amino acid residues of bacterial proteins and

plasma membrane proteins, leading to death of bacterial

cells. RNOS also directly damage bacterial DNA through

strand breaks, formation of basic sites, and deamination

of nucleotides.104 NO-NPs have been shown to inhibit the

growth of antibiotic-resistant strains of P. aeruginosa, E.faecalis, K. pneumoniae, and E. coli. When administered

at a concentration of 1.25-5 mM, NO-NPs successfully

killed MRSA, E. faecalis, and E. coli.105 (Fig. 3).

In addition, nanoantibiotics have advantages over con-

ventional antibiotics because they interact with multi-

ple biological pathways in bacteria and are stable for a

long time in terms of their action and storage. In addi-

tion, antibiotic NP polymers enhance the efficacy of

traditional antimicrobial agents not only through the addi-

tional antimicrobial activity of the NP polymers, but also

by increasing the solubility and efficiency of delivery of





the antimicrobial. Nylon-6 nano-fiber incorporated with

5,5-dimethyl hydantoin (DMH) exhibited strong antimi-

crobial activity compared with DHM alone.106

2.4. Nano-Based Diagnosis of Infectious DiseasesNPs with appropriate surface modifications are able to

interact with biomolecules such as proteins and DNA.45�107

The unique physical and chemical properties of NPs allow

accurate, rapid, sensitive, and cost-efficient diagnostics.

For example, NPs with enhanced fluorescent properties

can improve sensitivity in diagnostic molecular bioimag-

ing. In antibody-based diagnoses, primary antibodies rec-

ognize antigenic proteins of cells or viruses and secondary

antibodies recognize the primary antibodies, specifically

the constant regions. Labeling the secondary antibodies

with fluorescent NPs can remarkably enhance detection

sensitivity.108

Fluorescent silica NPs (FSNPs)98 have been devel-

oped to detect MTB. In this application, FSNPs encap-

sulate two organic and metallic fluorescent dyes, Tris

(2,2′bipyridyl) osmium bis (hexafluorophosphate) (OsBpy)

and Tris (bipyridine) ruthenium(II) dichloride (RuBpy),

that are excited by a single wavelength. These FSNPs

exhibit high signal amplification and photostability. MTB

is detected using anti-MTB primary antibody and a sec-

ondary antibody labeled with FSNPs for enhanced detec-

tion of anti-MTB antibody. Using this system, MTB was

detected in a mixture of bacteria and sputum with high

sensitivity and within only 4 hours.108

A system for the detection of anthrax protective agent

(PA) has been developed using fluorescence ELISA that

incorporated Eu(III) polymeric NPs. This system showed

approximately 100-fold higher sensitivity than conven-

tional ELISA.109�110 A rapid ELISA system to detect Her-

pes Simplex Virus type 2 (HSV-2) has been developed

using Au-NPs bound to anti-human IgG and allows detec-

tion of HSV-2 in 15–20 minutes using a test strip.111 MTB

DNA also can be detected rapidly and accurately using an

Au-NP–based colorimetric assay.112 A protein assay chip

using a signal amplification method involving NPs has

been developed for the detection of HBV and HCV.113

Quantum dots (Qdots) are special nano-crystal semicon-

ductors made of metals such as Si or Ge that range in

size from 1 nm to 10 nm.21 Qdots possess very strong

fluorescence intensity that makes them suitable for sen-

sitive image acquisition and signal amplification in real

time.80 Many Qdots have been developed to detect various

types of viral and bacterial proteins in order to diagnose

pathogenic diseases with enhanced sensitivity and speci-

ficity over conventional organic fluorophores. The Tripe

and Nie groups successfully demonstrated that dual core

Qdots could detect a single copy of virus or viral pro-

tein with high sensitivity and in real time.114 The dual

core Qdots were composed of two fluorescent NPs green

color and red one (40 nm carboxyl-modified fluorescent

NPs: GNPs, 505/51 and RNPs, 488/685) and streptavidin-

coated Qdots (488/605). These dual core Qdots were

used to label secondary antibodies that recognize anti-

bodies against respiratory syncytial virus (RSV).114�115

Qdots that create a barcode for multiplex identification of

biomolecules have been developed to identify multiple tox-

ins in blood.75 Barcodes have also been created using Qdots

(ZnS-capped CdSe Qdots) conjugated with three pathogen

antigens: HBsAg for HCV, HCV nonstructural protein 4

(NSP-4) for HCV, and glycoprotein 41 (gp41) for HIV.

This barcode-based multiplex identification system allowed

detection at a threshold of 10−10 to 10−12 M from 100 �lhuman serum spiked with corresponding viral antigens.80

Certain metallic NPs have a special optical property

known as surface plasmon resonance (SPR) that pro-

duces intense absorption when excited by electromagnetic

radiation.108 Gold NPs have been used for the detection of

DNA since 1996,116 and gold nano-wire arrays (GNWA)

linked with specific antibodies against E.coli have been

developed to detect urinary tract infection.117 Immuno-gold

silver staining with Au-NPs is very a sensitive method

for the detection of single molecules that does not need

advanced instruments and has been applied to the detec-

tion of HCV and HBV.113�118 Gold nano-rods have two

surface plasmon spectra: a strong and long wavelength

band at 600–950 nm and a short wavelength band at

520 nm. Non-linear optical properties (NLO) of gold nano-

rods vary with their shape and size and can be monitored

using the Hyper Rayleigh Scattering (HRS) technique. The

NLO properties of gold nano-rods allow them to be used

in bioconjugation-based diagnostic methods. For example,

HIV-1 DNA (gag gene) has been successfully quantified

by monitoring the light scattering pattern of dye-tagged

ssDNA gold nano-rods using HRS spectroscopy.119 The

detection limit of this method for the HIV-1 gag gene was

100 pM. This technique is highly sequence-specific; even

a single base pair mismatch results in a different light pat-

tern and can therefore be captured.

Polystyrene NPs loaded with Eu(III) ions have unique

photophysical properties such as sharp line-like emission

peaks, longer lifetime, and a large stroke shift. These

properties allow rapid and cheap detection of Anthrax

protective agent (PA) using these NPs. Polystyrene NPs

co-polymerized with acrylic acid have been used to

identify P. falciparum, the causative agent of malaria,

in the outfield.113

Surface Enhanced Raman Scattering (SERS) silver

nano-rod arrays have been used to track the molecular

fingerprints of several infectious pathogens.120 SERS is

a Raman spectroscopic technique that provides greatly

enhanced Raman signals from Raman-active analytic

molecules adsorbed on a rough metal surface or on nano-

structures such as silver nano-rods, silica nanotubes, or

carbon nanotubes. Gold nanowires coated with silica were

used to develop a sandwich DNA hybridization assay to





Figure 4. Test strip assay format.

Notes: Toxins are captured by the gangliosides attached on the liposome surface. The toxin-bound liposomes migrate through the nitrocellulose test

strip. Toxins bound to the liposomes are captured by anti-toxin antibodies in the analytical zone, producing a color change that indicates the presence

of toxins.124

detect multiple viruses.98 Nanowires made of different

metals by electrode position were used to study multiplex

detection of protein and nucleic acid based on the barcod-

ing phenomenon.121

Magnetic particles such as Fe3O4 or Fe2O3 also have

great potential for detecting food-borne pathogens such as

E. coli O157:H7 and Salmonella.122 Magnetic NPs coated

with antibodies are used for the detection of pathogens

by immunogenic separation. Vancomycin-conjugated FePt

magnetic NPs were developed to capture and iden-

tify vancomycin-resistant enterococci (VRE) and other

Gram-positive bacteria present at very low concentra-

tions in samples. Subsequently, these Fept@van biofunc-

tional magnetic NPs were combined with fluorescent

dyes for rapid detection of bacteria from human blood

samples.75�76 Biocompatible super paramagnetic iron oxide

(SPIO) nano-biosensors developed for the detection of

HSV-1 and adenoviruses were able to detect five viral par-

ticles in 10-�l serum samples without any PCR amplifica-

tion steps.77

Liposomes have become very versatile tools in

biomedical applications due to their enormous diversity

in structure and composition. Engineered liposomes are

able to mimic cells and recognize target toxins, and can

therefore be used for toxin detection. When such lipo-

somes were labeled with fluorescent markers (rhodamine

dyes) and used in a sandwich fluoroimmunoassay on

antibody-coated microtiter plates, they could detect the

cholera toxin with a threshold of 1 nM.123 In another

recent study, a sensitive bioassay system for cholera toxin

(CT) was developed using ganglioside GM1-labeled lipo-

somes (∼ 200 nm in diameter). In this sandwich assay,

CT bound to the liposomes was captured by immobilized

antibodies and detected as a colored band on a nitrocel-

lulose membrane strip, as shown in Figure 4. The limit

of detection was 10 fg/ml and the assay could be com-

pleted in 20 minutes.124 A similar assay was developed

to detect botulinum toxin (BT) using trisialoganglioside

GT1b, a receptor for BT. In this immunoassay, BT bound

to GT1b-liposomes was captured by immobilized anti-BT

antibodies and detected as a colored band on a nitrocellu-

lose membrane strip.125

3. CONCLUSIONSThis review presented current limitations of conventional

treatment and diagnostics as well as current advances

facilitated by nanoparticles to address the limitations.

The emerging field of nanotechnology addresses the cur-

rent limitations of conventional treatment and diagnostics.

Modern nano-based vaccines are more reliable than con-

ventional vaccines and now occupy almost 65% of the

worldwide vaccine market. The worldwide market value

of nanotechnology products has reached 11,671 million

US dollars and is expected to increase to 26,000 million

US dollars by 2015 with an annual growth rate of 11.1%.

Although nanotechnology already provides new directions

for the advancement of treatments and diagnostics for

infectious diseases, it should be developed further for

practical use in daily life. Furthermore, nanotechnology-

based therapeutics, vaccines, and diagnostics may foster

easy, cheap, safe, and portable use of end-products, which

will help control infectious diseases, especially in devel-

oping countries, and improve public health. Nanoparticles





make a great leap from traditional diagnosis and treatment

to more advanced and improved ones by allowing con-

trolling many parameters in diagnosis and treatment such

as controlled slow release of encapsulated drugs. For fur-

ther advance in nanoparticle-based technologies, it is very

essential to develop to design nanoparticles with a desired

function: efficient encapsulation of drugs, specific binding

to targets, on-site release, etc. So far, studies have replied

on empirical or intuitive approaches. We believe that in

order to further facilitate the advance of nanoparticle-based

approaches it is necessary to develop systematic and ratio-

nal design principles for nanoparticle design.

Acknowledgment: This work was supported by a grant

from the Basic Science Research Program (2011-0013819)

through the National Research Foundation of Korea

(NRF) funded by the Ministry of Education, Science and

Technology.

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Received: 5 October 2013. Accepted: 3 November 2013.


Nanotechnology for Diagnosis and Treatment of Infectious Diseases

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