Accepted Manuscript

Review

Applications of Nanoparticle Systems in Drug Delivery Technology

Syed A.A. Rizvi, Ayman M. Saleh

PII: S1319-0164(17)30179-2
DOI: https://doi.org/10.1016/j.jsps.2017.10.012
Reference: SPJ 658

To appear in: Saudi Pharmaceutical Journal

Received Date: 13 June 2017

Accepted Date: 22 October 2017

Please cite this article as: Rizvi, S.A.A., Saleh, A.M., Applications of Nanoparticle Systems in Drug Delivery
Technology, Saudi Pharmaceutical Journal (2017), doi: https://doi.org/10.1016/j.jsps.2017.10.012

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 Applications of Nanoparticle Systems in Drug Delivery Technology

Syed A. A. Rizvi1 & Ayman M Saleh2

1
Department of Pharmaceutical Sciences
College of Pharmacy, Health Professions Division
Nova Southeastern University
3200 South University Drive, Fort Lauderdale, FL 33328, USA
2
Department of Clinical Laboratory Sciences
College of Applied Medical Sciences
King Saud Bin Abdulaziz University for Health Sciences
King Abdullah International Medical Research Center (KAIMRC)
King Abdulaziz Medical City, National Guard Health Affairs
Mail Code 6610, P. O. Box 9515, Jeddah 21423, Saudi Arabia

*Correspondence Address:
1
Syed A. A. Rizvi, PhD, MBA, MS.
Department of Pharmaceutical Sciences
College of Pharmacy, Health Professions Division
Nova Southeastern University
3200 South University Drive, Fort Lauderdale, FL 33328, USA
Tel: +1 954-262-1542, Email: srizvi@nova.edu

2
Ayman M Saleh, PhD.
Department of Clinical Laboratory Sciences
College of Applied Medical Sciences,
King Saud Bin Abdulaziz University for Health Sciences
King Abdulaziz Medical City, National Guard Health Affairs, Mail Code 6610, P. O. Box
9515, Jeddah 21423, Saudi Arabia
Tel: +966 12-224-6666 Ext. 46090 and 45505, Email: salehay@ksau-hs.edu.sa
Abstract
The development of nanoparticle-based drug formulations has yielded the
opportunities to address and treat challenging diseases. Nanoparticles vary in size but
are generally ranging from 100-500 nm. Through the manipulation of size, surface
characteristics and material used, the nanoparticles can be developed into smart
systems, encasing therapeutic and imaging agents as well as bearing stealth property.
Further, these systems can deliver drug to specific tissues and provide controlled
release therapy. This targeted and sustained drug delivery decreases the drug related
toxicity and increase patient’s compliance with less frequent dosing. Nanotechnology
has proven beneficial in the treatment of cancer, AIDS and many other disease, also
providing advancement in diagnostic testing.

1. Introduction
Comparing current practice of medicine to that of the last century, one cannot
help but to notice innumerable advancements to address previously incurable diseases
(Sheingold and Hahn, 1960). Numerous new medications have been developed to
effectively treat complicated conditions, but at the same time some of them produce
severe side effects that the benefit does not always outweigh the risk (Liebler and
Guengerich, 2005). On the other hand, some drugs have been proven to be very
effective in vitro but cannot withstand the endogenous enzymes found within the
gastrointestinal (GI) tract (if taken orally), deeming them nearly worthless in vivo
(Rostami-Hodjegan and Tucker, 2007). While incredible progress has been made in
identifying drug targets, designing and making better drug molecules; there is still room
to improve the drug delivery systems and targeting (Tiwari et al., 2012).
Within past few decades, nanotechnology, in particular manufacturing of
nanoparticles has found an unprecedented attention in broad areas of science
(Bhattacharyya et al., 2009). A PubMed search (“nanoparticles”) reveals, last year alone
(2016), there were “19338” articles published related to various aspects of nanoparticle
technology (PubMed, 2017). The clever use of nanoparticles has revolutionized how
drugs are formulated and delivered. Nanotechnology is a multi-disciplinary scientific
field applying engineering and manufacturing principles at the molecular level (Emerich
and Thanos, 2006). By applying nanotechnology to medicine, nanoparticles have been
created to mimic or alter biological processes (Singh and Lillard, 2009). Nanoparticles
are solid, colloidal particles with size range from 10 nm to <1000 nm; however, for
nanomedical application, the preferential size is less than 200 nm (Biswas et al., 2014).
One of the most significant areas of study has been in the creation of nanoparticle drug
delivery systems. This succinct review will focus on the desirable characteristics for
successful nanoparticle based drug delivery systems as well as the various disease
states in which these nanoparticle systems have shown promise.

2. Necessity for nanoparticle-based drug formulations

There are various reasons why using nanoparticles for therapeutic and
diagnostic agents, as well as advancement of drug delivery, is important and much
needed. One of them is that, traditional drugs available now for oral or injectable
administration are not always manufactured as the optimal formulation for each product.
Products containing proteins or nucleic acids require a more innovative type of carrier
system to enhance their efficacy and protect them from unwanted degradation (Vo et
al., 2012). It is notable that the efficiency of most drug delivery systems is directly
related to particle size (excluding intravenous and solution). Due to their small size and
large surface area, drug nanoparticles show increase solubility and thus enhanced
bioavailability, additional ability to cross the blood brain barrier (BBB), enter the
pulmonary system and be absorbed through the tight junctions of endothelial cells of the
skin (Kohane, 2007). Specifically, nanoparticles made from natural and synthetic
polymers (biodegradable and non-biodegradable) have received more attention
because they can be customized for targeted delivery of drugs, improve bioavailability,
and provide a controlled release of medication from a single dose; through adaptation
the system can prevent endogenous enzymes from degrading the drug (Zhang and
Saltzman, 2013). Secondly, the development of new drug delivery systems is providing
another advantage for pharmaceutical sales to branch out. Innovative drug delivery is
driving the pharmaceutical companies to develop new formulations of existing drugs.
While these new formulations will be beneficial to the patients, it will also create a
powerful market force, driving the development of even more effective delivery methods
(Emerich and Thanos, 2007).
Furthermore, not only will the companies thrive to develop new formulations for
their own “intellectual property,” but will have motivation due to patent expirations
(Osakwe and Rizvi, 2016). The benefit of pharmaceutical companies taking advantage
of this new technology is that nanotechnology gives new life to those drugs those were
previously considered unmarketable due to low solubility and bioavailability, and high
toxicity and marked side effects (Onoue et al., 2014). Finally, we would like to highlight
a very recent article from Prof. Robert Langer’s group, at the Massachusetts Institute of
Technology (Kakkar et al., 2017), with an up-to-date survey of the types of polymeric
systems used in the drug delivery.

3. Characteristics of Nanoparticle Drug Formulations

Before defining exactly what an ideal nanoparticle-based drug delivery system is
made of, understanding how the body handles the exogenous particulate matter is
warranted. Nanoparticles can enter the human body, via three main route, direct
injection, inhalation and oral intake. Once, they enter systemic circulation, particle-
protein interaction is the first phenomenon taking place before distribution into various
organs (Mu, et al., 2014; Prado-Gotor and Grueso, 2011). Absorption from the blood
capillaries allows the lymphatic system to further distribute and eliminate the particles.
This system has three main functions, two of which pertain to drug delivery. The first,
fluid recovery, involves the filtering of fluids by the lymphatic system from blood
capillaries. The second encompasses immunity, and may be the most relevant to this
topic. As the system recovers excess fluid, it also picks up foreign cells and chemicals
from the tissues. As the fluids are filtered back into the blood, the lymph nodes detect
any foreign matter passing through (Park, et al., 2016). If something is recognized as
foreign, macrophages will engulf and clear it from the body. This tends to be the
struggle with nanoparticle based drug delivery; however, clearance can be influenced
by the size and surface characteristics of particles, which will be elaborated on in
following subsections (Alexis, et al., 2008).

3.1. Size of particle

The shape and size of nanoparticles affects how cell in the body “see” them and
thus dictate their distribution, toxicity, and targeting ability. Most importantly,
nanoparticles can cross the BBB providing sustained delivery of medication for diseases
that were previously difficult to treat (McMillan, et al., 2011). Not only is it possible to
reach new targets, but this technique can be manipulated to control drug distribution. It
has been reported that 100 nm nanoparticles exhibited a 2.5-fold greater uptake
compared to 1 μm diameter particles and a 6-fold great uptake than a 10 μm particles
(Desai, et al., 1997).
It has been discussed how important the nanoparticle drug delivery systems are,
but these systems would be on no use if the drug is not released or released effectively
(Chavanpatil, et al., 2007). As particles size get smaller, their surface area to volume
ratio gets larger. This would imply that more of the drug is closer to the surface of the
particle compared to a larger molecule. Being at or near the surface would lead to faster
drug release (Buzea, et al., 2007). It would be beneficial to create nanoparticle systems
that have a large surface area to volume ratio; however, toxicity must always be
monitored. As mentioned earlier, the size of the nanoparticle determines biological fate.
Remember that the vascular and lymph systems are responsible for the filtering and
clearance of foreign matter and chemicals. This is yet another factor that must be
engineered into the ideal nanoparticle system. It has been shown that particles 200 nm
or larger tend to activate the lymphatic system and are removed from circulation quicker
(Prokop, et al., 2008). Thus, from the literature evaluation and discussion so far, it is
clear as though the optimum size for a nanoparticle is approximately 100 nm. At this
size, the particle could pass through the BBB, sufficient amount of drug delivery due to
high surface area to volume ratio, and avoiding immediate clearance by the lymphatic
system.
3.2. Surface properties
It has been noted how size can influence the performance of nanoparticle-based
drug formulations; however, manipulation of surface characteristics is another
opportunity to generate the ideal system (Bantz, et al., 2014). In order to create an
optimum nanoparticle drug delivery system, the incorporation of appropriate targeting
ligands, surface curvature and reactivity is important to address the prevention of
aggregation, stability, and receptor binding and subsequent pharmacological effects of
the drug (Khanbabaie and Jahanshahi, 2012).
First, clearance of nanosystems must be addressed. Since nanoparticles can be
recognized by the lymphatic system, they are subject to the body’s natural immune
response to foreign matter. The more hydrophobic a nanoparticle is, the more likely it is
to be cleared due to higher binding of blood components (Kou, 2013). As hydrophobic
nanoparticles are cleared easily, it seems logical to assume that making their surface
hydrophilic would increase their time in circulation. In fact, coating the nanoparticles
with polymers or surfactants or creating copolymers like polyethylene glycol (PEG),
diminishes the opsonization), polyethylene oxide, polyethylene glycol (prevents hepatic
and splenic localization), polyoxamer, poloxamine, and polysorbate 80 has been proven
valuable (Araujo, et al., 1999; Labhasetwar, et al., 1998). PEG is hydrophilic and
relatively inert polymer that when incorporated in the nanoparticle surface, hinders the
binding of plasma proteins (opsonization), and thus preventing substantial loss of the
given dose. PEGylated nanoparticles are often referred as “stealth” nanoparticles,
because without opsonization, they remain undetected by the reticuloendothelial system
(RES) (Li and Huang, 2010; Angra, et al., 2011). By creating polymer complexes,
clearance issues have been addressed, but aggregation is still a concern with small
particles due to large surface area. Particularly, nanoparticles such as dendrimers,
quantum dots, and micelles are especially prone to aggregation. Several strategies
have been employed to prevent aggregation and call for particles coating with capping
agents and altering the zeta potential (surface charges) (Li, and Kaner, 2006).
 Overall, these methods and theories can be summarized into one idea: the size
of the particle must be large enough to avoid leakage into blood capillaries, but not too
large to become susceptible to macrophage clearance. By manipulating the surface, the
extent of aggregation and clearance can be controlled (Sykes, et al., 2016).

3.3. Drug loading and release

The size and surface properties of nanoparticles have been explored to optimize
bioavailability, decrease clearance, and increase stability. By controlling these
characteristics, it is possible to get the drug to tissues in the body that may have been
inaccessible before. However, there is no significance of this practice if the drug cannot
then be released from the nanoparticle matrix. The release of drug from the
nanoparticle-based formulation depends on may factors including, pH, temperature,
drug solubility, desorption of the surface-bound or adsorbed drug, drug diffusion through
the nanoparticle matrix, nanoparticle matrix swelling and erosion, and the combination
of erosion and diffusion processes (Son, et al., 2017; Mura, et al, 2013; Siepmann and
Göpferich, 2001).
Depending on the type of nanoparticle being used, the release of drug will differ.
The prepared polymeric nanoparticles can be called nanocapsules or nanospheres
based on their composition. Nanospheres are homogeneous system such that the
polymer chains arrange in a similar fashion to surfactants in micelle formation (phase-
separated from the bulk solution). While, nanocapsules are heterogeneous system,
such that the drug is inside a reservoir composed of the polymer (like vesicle) (Mora-
Huertas, et al., 2010).
In relation to nanospheres, which are matrix system where the drug is physically
and uniformly dispersed, drug is released by erosion of the matrix. There is a rapid
burst of drug release related to weakly bound drug to the large surface area of the
nanoparticle followed by a sustained release (Lee and Yeo, 2015). On the other hand,
if nanocapsules are used, the release is controlled by drug diffusion through the
polymeric layer and thus, drug diffusibility through that polymer is definitely a
determining factor of its deliverability. If there are ionic interactions between the drug
and polymer, they will form complexes which inhibit the release of drug from the
capsule. This can be avoided by adding other auxiliary agents such as polyethylene
oxide-propylene oxide (PEO-PPO). This will decrease the interactions between the drug
and capsule matrix allowing for greater release of drug to target tissues (Calvo, et al.,
1997).

4. Targeted Drug Delivery

After recognizing the importance of nanoparticle manipulation to achieve a
successful drug delivery system, the next logical step is the development of targeted
drug delivery. The nanoparticles can breach the inflamed or damaged tissue due to
larger epithelial junctions. This penetration can occur passively or actively. Active
targeting is when the drug carrier system is conjugated to a tissue or cell-specific ligand,
while passive targeting is when nanoparticle reaches the target organ due to the leaky
junctions (Varshosaz and Farzan, 2015).
An ideal nanoparticle drug delivery system (Figure 1) should be able to reach,
recognized, bind and deliver its load to specific pathologic tissues, and minimize or
avoids drug induced damage to healthy tissues. Thus, coating specific targeting
ligand(s) on the surface of nanoparticles is the most common strategy. These targeting
ligands could be in the form of small molecules, peptides, antibodies, designed proteins,
and nucleic acid aptamers (Liu, et al., 2009; Friedman, et al., 2013).
Small organic molecules are the most commonly employed targeting agents due
to relative ease of preparation, stability, and control of conjugation chemistry with.
These targeting ligands may not have desired specificity and affinity. Biotin (vitamin H),
due to very high affinity for streptavidin has been widely used for conjugation with
nanoparticles (Pramanik, et al., 2016). Folic acid (vitamin B9) has excessive affinity for
endogenous folate receptor and thus has been investigated for targeting many types of
cancers where folate receptors are highly expressed (Zhao, et al., 2008). Similarly,
many other task specific carbohydrates, short peptides, antibodies and small molecules
have been designed and employed (Friedman, et al., 2013).
 Another useful discovery to aid in the targeted delivery of drugs is liposomes.
Since they mimic the cell membrane, one can design specific lipid monomer to tailor
physicochemical properties such as size and charge and can also incorporate surface
targeting ligands as discussed above (Kelly, et al., 2011). This system over additional
advantage, since liposomal composition is similar to the targeted cell membrane, an
enhanced lipid-lipid exchange occurs. This speeds up the convective flux of lipophilic
drugs from the liposomal lipid layer into the targeted cell membrane (Singh and Lillard,
2009; Kelly, et al., 2011; Pattni, et al., 2015).

Figure 1. Representation of a smart multifunctional drug loaded nanoparticle, decorated

with various moieties for targeting, imaging and stealth properties.

5. Application of Nanoparticle Technology

5.1. Cancer Therapy

 The type of therapy used to treat cancer patients today, has saved lives of many
individuals; however, the side effects of treatment are harsh, affecting the entire body
due to non-specificity of the chemotherapeutic agents. Cancer is a very complicated
biological phenomenon, and can be considered a disease of many diseases. One of the
hallmark of cancerous cells is that they divide and multiply rapidly and out of control
(Hanahan and Weinberg, 2011). Current chemotherapy is mainly aimed at destroying all
rapidly dividing cells. The downside of this therapy is that the body’s other rapidly
proliferating cells, such as in the hair follicles and intestinal epithelium are also killed off,
leaving the patient to cope with life altering side effects (Baudino, 2015). The
development of nanoparticles has provided a new avenue for chemotherapy. With
smartly designed nanoparticles, targeted drug delivery at the tumor site or a certain
group of cells do largely avoid the toxic effects to other normal tissues and organs
(Shen, et al., 2016; Huang, et al., 2015). There have been several systems tested to
provide this type of therapy.
Micelles and liposomes offer another option for delivery of chemotherapeutic
agents. Additionally, micelles are also a great way to make insoluble drugs soluble due
to their hydrophobic core and hydrophilic shell. If the micelle’s surface is further
PEGylated, it increases the ability of the nanocarriers to get through fenestrated
vasculature of tumors and inflamed tissue through passive transport, thus resulting in
higher drug concentration in tumors. As of now, several polymeric micelles containing
anticancer drugs, NK012, NK105, NK911, NC-6004, and SP1049C are under clinical
trials (Oerlemans, et al., 2010) and one such system, Genexol-PM (paclitaxel) is
approved for breast cancer patients (Zhang, et al., 2014).
Dendrimers are highly branched macromolecules with many functional groups
available for the attachment of drug, targeting and imaging agents and their absorption,
distribution, metabolism and elimination (ADME) profile is dependent upon various
structural feature (Somani and Dufes, 2014; Kaminskas, et al., 2011). A polyfunctional
dendrimer system has been reported for successful localization (Folic acid), imaging
(fluorescein) and delivery of the anticancer drug methotrexate in vitro (Quintana, et al.,
2002). Nanoparticle therapeutics based on dendrimers can improve the therapeutic
index of cytotoxic drugs by employing biocompatible components, and the surface
derivatization with PEGylation, acetylation, glycosylation, and various amino acids
(Baker, 2009; Cheng, et al., 2011).
While there are several other forms of nanoparticles that have shown promise in
cancer treatment, one of the most recent system is the carbon nanotubes. Carbon
nanotubes (CNTs) is an allotropic form of carbon with cylindrical framework and
deepening on number of sheets in concentric cylinders, they can be classified as single-
walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs)
(Rastogi, et al., 2014; Sanginario, et al, 2017). Since Carbon nanotubes have very
hydrophobic hollow interior, water insoluble drugs can easily be loaded them. The large
surface area allows for outer surface functionalization and can be done specifically for a
particular cancer receptor as well as contrast agents (Dinesh, et a., 2016).
Finally, Buckminsterfullerene C60 (spherical molecule) and its derivatives are
evaluated for the treatment of cancer (Murugesan, et al, 2007; Chen, et al, 2012).
Fullerene C60 can bind up to six electrons, and thus act as an excellent scavenger of
reactive oxygen species (ROS) as well (Prylutska, et al, 2008). It has been reported that
fullerene nanocrystals (Nano-C60) can enhance the cytotoxicity of chemotherapeutic
agents and thus a Nano-C60 adjunct chemotherapy can be further evaluated (Zhang, et
al, 2009). Prylutska, et al, (2015) conducted another study using the complex of
Fullerene C60 with Doxorubicin and noted the tumor volumes of the treated rats
(C60  +  Dox) to be 1.4 times lower compared to the control group (untreated rats).
Furthermore, the mechanism of action of C60  +  Dox complex is thought to be via its
direct action on tumor cells as well as immunomodulating effect.

5.2. Diagnostic Testing

The use of nanoparticle for diagnostic purposes is an area that currently
unavailable for clinical application, but heavily explored in academia (Kolluru, et al.,
2013). Since current technology for diagnostic testing is hindered by the inadequacies
of fluorescent markers including fading of fluorescence after single use, color matching,
and restricted use of dyes due to a bleeding effect, fluorescent nanoparticles provide
researchers with the answer to overcome these disadvantages (Wolfbeis, 2015).
 One important breakthrough was the discovery of quantum dots which can be
custom-made in many sharply defined colors. Their absorption spectrum ranges from
UV to a wavelength within visible spectrum and provide high quantum yield, tunable
emission spectrum and photostability. Size of the nanodot determines where in the
spectra that individual particle falls. Larger particles have longer wavelengths and
emission is narrow (Emerich and Thanos, 2006, Li and Zhu, 2013; Michalet, et al.,
2005). Tagging of the quantum dots has several advantages. First, they are excitable
using white light. Secondly, they can be linked to biomolecules that can spend consider
amount of time in the living system to probe various bio-mechanisms. This technology
further allows one to monitor many biological events simultaneously by tagging various
biological molecules with nanodots of a specific color (Datta and Jaitawat, 2006).
Recently, theranostic nanoparticles, nanoparticles that can be used for treatment
as well as diagnoses have gain much attention (Janib, et al., 2010). This strategy has
been realized in many classes of nanoparticles including, drug conjugates, dendrimers,
surfactant aggregates (micelles and vesicles), core-shell particles, and carbon
nanotubes. By combing both drug and imaging agent in one smart formulation various,
it is possible to monitor the pathway and localization of these nanoparticle at the target
site as well drug action to assess therapeutic response (Bhojani, et al., 2010).

5.3. HIV and AIDS Treatment

Infection with human immunodeficiency virus (HIV), if not addressed can lead to
acquired immune deficiency syndrome (AIDS) is a devastating disease where an
individual’s immune system is almost destroyed (Moss, 2013). When treatment was first
developed for this disease, it was painstakingly involved, where most patients could be
taking 30 - 40 pills a day. In the past decade, there have been advancements in
therapeutics to reduce the pill count down to just a few each day (Bartlett and Moore,
1998). Research has shown a way to make this therapy even more effective by creating
polymeric nanoparticles that deliver antiretroviral (ARV) drugs intracellularly as well as
to the brain (Mamo, et al., 2010). This technology can also be used in adjunct with
vaccinations to prevent HIV infections (Khalil, 2011).
 Antiretroviral drugs that are used to treat HIV, can be categories depending on
the stages of HIV life cycle they work most suitably on. In order to prevent the
development of resistance and aggressively counter the HIV progression, a combination
of multiple drugs (three or more) are used, this known as highly effective antiretroviral
therapy (HAART) (Crabtree-Ramírez, et al., 2010). Nanotechnology has played a
pivotal role in delivering the antiretroviral drugs and improving compliance (Jayant,
2016). Antiretroviral drugs must be able to cross the mucosal epithelial barrier when
taken orally or other non-parental routes (suppository and patches, etc.). Lymphoid
tissues are major sites for HIV to infect and thrive. A number of reports have
demonstrated that nanoparticle loaded with antiretroviral drugs were able to target
monocytes and macrophages in vitro (Shah and Amiji, 2006; Mallipeddi and Rohan,
2010). A prime example of superiority and success of nanoparticle system for sustained
and targeted drug delivery was reported by Destache, et al. (Destache, et al., 2009).
The investigators used poly(lactic-co-glycolic acid) (PLGA) to prepare nanoparticles
entrapping three antiretroviral drugs, ritonavir, lopinavir, and efavirenz. The nanoparticle
system yielded sustained drug release for over 4 weeks (28 days), while free drugs
were eliminated within 48 hrs (2 days). The Central nervous system (CNS) is another
site for HIV to inoculate and thrive resulting in serious HIV-associated neurocognitive
disorder (HAND) (Spudich and Ances, 2011). Nanoparticles are a known to be able to
cross BBB by endocytosis/phagocytosis and many reports exist showing successful
delivery of anti-HIV medications (Rao, et al., 2009; Nowacek, et al., 2010).

5.4. Nutraceutical Delivery

Nutraceuticals are food derived, standardized components with noticeable health
benefits. They are commonly consumed as complement to various allopathic treatments
as well as to provide extra health benefits and decrease risks of several chronic
illnesses (Aggarwal, et al., 2009). Similar to the case of any other drug, the
bioavailability and thus efficacy of orally consumed nutraceuticals is affected by food
matrices interactions, aqueous solubility, degradation/metabolism, and epithelial
permeability (McClements et al., 2015.). Most nutraceuticals are lipophilic molecules,
such as fat-soluble vitamins (A, D, E and K), polyunsaturated lipids and other
phytochemicals. Nanotechnology again offers comprehensive assistance and most of
the investigations have been aimed at improving the dissolution mechanisms of
nutraceuticals via nanoparticle formulations (Acosta, 2009; McClements, 2015).
A large number of nutraceuticals, posse anti-inflammatory, antioxidative,
antiapoptotic, and antiangiogenic activities, among those, the most prominent and
studied is curcumin (diferuloylmethane). It is practically water-insoluble and has very
poor bioavailability, thus various methods have been implemented to address this issue,
such as liposomes, phospholipid vesicles, and polymer-based nano-formulation
(Mohanty, et al., 2010.; Carvalho, et al., 2015). A 9-fold higher oral bioavailability of
curcumin was observed when compared to curcumin co-administered with piperine
(absorption enhancer) (Shaikh, et al., 2009.). Another study of colloidal nanoparticles of
curcumin dubbed, Theracurmin when compared to curcumin powder, exhibited 40-fold
higher area under the curve (AUC) in rats and 27-fold higher in healthy human
volunteers as well as inhibitory actions against alcohol intoxication (Sasaki, et al., 2011).
Resveratrol is an important non-flavonoid polyphenol, naturally occurs in several
plants but most abundantly found in Vitis vinifera, labrusca, and muscadine grapes
(Celotti and Ferrarini, 1996.). It is known for antioxidant, cardioprotective, anti-
inflammatory and anticancer activities (Summerlin, et al., 2015). Resveratrol has low
solubility, with decent bioavailability, however, it is rapidly metabolized and eliminated
(Walle, 2011; Kapetanovic, et al., 2011) from the body. There are two geometric
isomers of resveratrol (cis- and trans), however the more abundant and bioactive trans-
resveratrol, is photosensitive, converters to cis-resveratrol in the presence of light (Trela
and Waterhouse, 1996). Many nanoformulations of resveratrol to improve the
pharmacokinetic profile and bioavailability have been reported. These include polymeric
nanoparticles (da Rocha Lindner and Bonfanti Santos, 2015; Sanna et al., 2013), Zein
based nanoparticles (Penalva, et al, 2015), nanoemulsions (Sessa, et al., 2013),
liposomes (Catania, et al, 2013), cyclodextrins (Venuti, et al., 2014), and dual
nanoencapsulation methods (Soo, et al., 2016). Recently, neuroprotective effects of
resveratrol were evaluated by preparing solid lipid nanoparticles decorated with
apolipoprotein E for LDL receptor recognition on the blood-brain barrier (Neves, et al.,
2015).

6. Conclusion
Nanotechnology is truly a multidisciplinary science where chemists, physicist,
biologists and pharmaceutical scientist all have played major roles to develop novel
treatment and diagnosing modalities. It is evident through this review that application of
nontechnology in drug delivery and medicine has paved new pathways and opened
many doors for providing customizable and safer treatment option. The treatment of
cancer and HIV/AIDS, non-invasive imaging as well as nutraceutical delivery have all
progressed with the application of nanotechnology. Ultimately, through the manipulation
of molecular size and surface properties, researchers are able to deliver drugs for
longer period of time with less frequent dosing (sustained release) and with greater
precision and penetration in difficult to access tissues.

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