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Surigao del Sur State University

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Website: sdssu.edu.gov.ph

THE USE OF NANOTECHNOLOGY IN THE TREATMENT OF DIABETES MELLITUS

A SYNTHESIS ON CONCEPTS IN BIOLOGY AND ECOLOGY

Submitted to

ROXAN G. EUPEÑA, PhD

Graduate Faculty/ Professor of
SURIGAO DEL SUR STATE UNIVERSITY
Tandag City, Surigao del Sur

In partial fulfillment of the Requirement for

SCIED 208 (CONCEPTS IN BIOLOGY AND ECOLOGY)

By:
MARIBETH J. CUSAP
JOYBIE LOAYON
MST-SciEd
 THE USE OF NANOTECHNOLOGY IN THE TREATMENT OF DIABETES

Diabetes is the eighth driving reason for death in the Philippines, with 3.7 million
cases in the most recent year alone. What's more, at the momentum rate Filipinos are
building up the disease, the International Diabetes Federation evaluates that the
Philippines might be among the top 10 nations with the most instances of the sickness by
2045. Diabetes, basically, is a metabolism disorder described by lacking the creation or
use of insulin by the body, bringing about expanded sugar levels in the blood and pee.
Left unchecked, the results can incorporate long haul harm and disappointment of organs,
particularly the eyes, kidneys, nerves, veins, and appendages. (Ku & Kegels, 2013)

There are two kinds of diabetes: Type 1, in which the body's safe framework
assaults the cells that produce insulin; and the more typical Type 2, where the body's
cells don't create enough insulin or don't respond to the insulin. Diabetes, especially Type
2 can be moderated from the get-go—or forestalled completely—with a solid way of life.
(Mayfield, 1998)

Mortality caused by diabetes in the Philippines

Source: https://www.researchgate.net/figure/3-Mortality-Rate-from-Diabetes-Mellitus-
Philippines-2008-2013_fig30_319998833
1.0 Definition of Nanotechnology

Nanotechnology alludes comprehensively to a field of applied science and

innovation which the primary objective is the control of issue on the atomic level in scales
smaller than 1 micrometer, regularly 1 to 100 nanometers, and the creation of gadgets
inside that size range. It is a profoundly multidisciplinary field, drawing from fields, for
example, applied material science, materials science, colloidal science, gadget material
science, supramolecular science, and even mechanical and electrical building. (Porter
et.al, 2008) (Roco,2011)

Nanotechnology can be viewed as an augmentation of existing sciences into the

nanoscale or as a recasting of existing sciences utilizing a more up to date, increasingly
present-day term. Two principal approaches are utilized in nanotechnology. In the "base
up" approach, materials and gadgets are worked from atomic segments that amass
themselves artificially by standards of sub-atomic acknowledgment. In the "top-down"
approach, nano-objects are built from bigger substances without nuclear level control.
(Clever & Shinonoya, 2010)

The impulse for nanotechnology originates from a reestablished enthusiasm for

colloidal science, combined with another age of explanatory instruments, for example, the
nuclear power magnifying lens (AFM), and the filtering burrowing magnifying instrument
(STM). Joined with refined procedures, for example, electron pillar lithography and
atomic shaft epitaxy, these instruments permit the conscious control of nanostructures
and prompted the perception of novel marvels. (Whitesides,2005)

In spite of the incredible guarantee of various nanotechnologies, for example,

quantum spots and nanotubes, genuine business applications have chiefly utilized the
upsides of colloidal nanoparticles in mass structure, for example, suntan salve,
beautifiers, defensive coatings, and stain-safe garments. Present-day manufactured
science has arrived at where it is conceivable to get ready little particles to practically any
structure. (Whitesides,2005)
 These strategies are utilized today to deliver a wide assortment of helpful synthetic
concoctions, for example, pharmaceuticals or business polymers. This capacity brings
up the issue of stretching out this sort of control to the following bigger level, looking for
strategies to collect these single atoms into supramolecular gatherings comprising of
numerous particles orchestrated in a well-characterized way. These methodologies use
the ideas of sub-atomic self-get together as well as supramolecular science to naturally
mastermind themselves into some helpful adaptation through a base up approach.
(Daniel & Astruc, 2004)

The idea of sub-atomic acknowledgment is particularly significant: particles can be

planned with the goal that a particular compliance or course of action is supported due to
non-covalent intermolecular powers. The Watson-Crick base-matching standards are an
immediate aftereffect of this, similar to the explicitness of a catalyst being focused to a
solitary substrate, or the particular collapsing of the protein itself. (Chang et.al, 2009)

2.0 Nanotechnology in the Diabetes Research

Nanotechnology in diabetes investigation has encouraged the advancement of

novel glucose estimation and insulin conveyance modalities which hold the possibility to
significantly improve quality of life for diabetics. Ongoing advancement in the field of
diabetes investigation at its interface with nanotechnology is the core interest.
Specifically, researchers inspect glucose sensors with nanoscale segments including
metal nanoparticles and carbon nanostructures. The expansion of nanoscale parts
regularly builds glucose sensor affectability, transient reaction, and can prompt sensors
that encourage constant in vivo glucose checking. Moreover, we review nanoscale ways
to deal with "shut circle" insulin conveyance procedures which consequently discharge
insulin because of fluctuating blood glucose levels. "Shutting the circle" between blood
glucose level (BGL) estimations and insulin organization by expelling the necessity of
patient activity holds the possibility to drastically improve the wellbeing and quality of life
among diabetics (Cash & Heather, 2010) (Mo, et.al, 2014). The following figure shows
the research themes commonly made for diabetes:
Figure 1 Schematic of research themes using nanotechnology for diabetes

treatment.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478103/#!po=7.35294

3.0 Nanotechnology enables to monitor glucose

Precise and frequent glucose estimations are the premise of contemporary

diabetes management. In any case, it is normally recognized that contemporary clinical
glucose estimation frameworks are an annoyance to the patient because of successive
and difficult needle sticks, and the present standard of discontinuous testing can miss
perilous changes in blood glucose concentration.(Pickup et.al, 2008) (Chertok et.al, 2013)
In this manner, one of the most huge difficulties in diabetes inquire about is the
advancement of glucose sensors which accomplish precise glucose estimations
effortlessly and much of the time, with the objective of nonstop glucose estimation. A wide
assortment of glucose detecting modalities have been accounted for over the most recent
two decades, and regularly utilize Concanavalin A (Con A), phenylboronic corrosive
(PBA), or most ordinarily, Glucose Oxidase (GOx) as a sensor for distinguishing glucose
in arrangement. Basic meddling species in blood and other natural liquids incorporate
Uric and Acetic acids, just as different starches, for example, Fructose, Lactose, and
Sucrose (Bratie et. al, 2012) (Yetisen et.al, 2014) (Veetil et.al., 2012)

3.0 Measuring of Glucose through Electrochemical Procedures

The great conductivity and synergist capacity of nanoscale carbon structures has
prompted their utilization in an assortment of glucose detecting modalities (Barone et.al,
2005) (Li et.al, 2003). Moreover, electrically coupling glucose oxidase to nanoscale
carbon structures regulates the electrical opposition of the structures (Besteman et.al,
2003). The first to distribute look into on utilizing a solitary carbon nanotube as a biosensor
was Besteman, et al., who immobilized GOx on a semiconductor carbon nanotube by
means of 1-pyrenebutanoic corrosive succinimidyl ester, and found that the conductivity
of the nanotube was associated to the movement of the immobilized GOx's reaction to
the expansion of glucose. The expansion of 0.1 mM glucose arrangement brought about
a surmised 10% expansion in the conductivity of the GOx-nanotube complex. The
framework likewise showed a solid affectability to the pH of the encompassing solution
(Besteman et.al, 2004)
Figure 2: Experiment of Yang et.al on improving the sensitivity of glucose sensors

Source: Yang et.al, 2014

Yang, et al explored how nanowires can influence the affectability of amperometric

glucose sensors. In this test, two kinds of sensors were built up; the first was framed by
immobilizing GOx inside a mass hydrogel, and the second was shaped by immobilizing
GOx on the outside of conductive nanowires. The figure above portrays a schematic of
the two sorts of glucose fixation sensors: (a–c) A mass hydrogel glucose sensor with
installed GOx. (a,d–g) A nanowire glucose sensor with implanted GOx. (h,i) The glucose
sensor device. (j–k) The mass hyrdogel-GOx detecting framework. (I–m) The nanowire-
GOx based glucose detecting framework. The nanowire-based sensor was more delicate
than the mass film sensor, which was credits to its bigger surface area, expanded GOx
stacking limit, and lower electrical obstruction. (Yang et.al, 2014)

4.0 Shut Circle Insulin Delivery through Nanotechnology

An appealing option in contrast to conventional insulin infusions is "shut circle"

frameworks which constantly screen blood glucose and discharge insulin in a self-
managed style. There are a few advantages of such a framework over the conventional
open-circle framework, including more tightly control of BGLs, which can decrease the
inconveniences normal for diabetes (New England Journal of Medicine, 1993) Shut circle
frameworks may likewise prompt a reduction in the measurements of insulin, and lessen
the quantity of hypoglycemic and hyperglycemic occasions.

5.0 Islet Cell Microencapsulation- Serves as artificial Pancreas

Encapsulating the body's own insulin creating β-cells inside semi-penetrable

polymer grids, for example, alginate hydrogel, is an appealing alternative for shut circle
insulin delivery. This procedure requires the epitome of β-cells inside a semi-porous film
that shields the cells from have invulnerable reactions while permitting small particles,
supplements, and insulin to latently diffuse over the layer. Structuring such a film is a
mind-boggling challenge and is being drawn closer from a few points of view. One of the
most critical difficulties to this methodology is conquering the host's safe reaction to
embedding remote islet cells. Commonly, the cells are quickly overwhelmed by fibrotic
abundances because of an insusceptible response (Dang et.al, 2013)

Another strategy for typifying islet cells is the Layer by Layer (LbL) deposition of a
semi-permeable film onto the cells (Pickup, 2008). A relentless test of utilizing LbL
testimony for islet cell epitome is maintaining a strategic distance from the utilization of
polyionic polymers, which are cytotoxic (Teramura et.al, 2008) (Wilson et.al, 2011).
Elective restricting methodologies are expected to make LbL coatings on the cells that
have expanded strength and diminished cytotoxicity. As of late, Gattas-Asfura and
associates detailed another LbL method using interpolymeric covalent connecting to
improve the strength of the LbL coatings (Gatas Asfura et.al, 2013) Alginate and
poly(amidoamine) (PAMAM) dendrimers were functionalized with corresponding
Staudinger ligation gatherings: azide and methyl 2-(diphenylphosphino) terephthalate.
Covalent linkages and electrostatic forces between the films expanded the dependability
and thickness of the resultant bilayer. This bioorthogonal functionalization strategy for
interpolymeric connecting likewise fills in as a technique for functionalizing the outside of
the islet and can be adjusted to incorporate auxiliary helpful operators, for example,
immunosuppressant drugs or bioactive gatherings that upgrade the nutrient.

6.0 Glucose-sensitive Insulin Delivery

Figure 3: The schematic representation on Glucose-sensitive Insulin Delivery

Source: Wiley Interdiscip Rev Nanomed Nanobiotechnol.

Artificial shut circle frameworks are frequently portrayed by their strategy for
glucose identification. Glucose can be distinguished through enzymatic strategies utilizing
compounds, for example, glucose oxidase (GOx), Binding of glucose to manufactured
gatherings, for example, those in Phenylboronic corrosive (PBA), or official to glucose
restricting proteins, for example, Concavalin A (Con A)
6.1 Glucose Binding Protein (GBP) Systems

Glucose binding proteins can tie to glucose or glucosyl moieties in glycopolymers

(Mo et.al, 2014). The most widely recognized class of glucose restricting proteins are
lectins. Lectins are a group of proteins that can tie to sugars and have a huge job in cell
signaling. The most widely recognized lectin utilized for insulin conveyance frameworks
is Concanavalin A (Con A). It is the favored GBP on account of its high liking for glucose.
Con A can tie to gluconic corrosive altered insulin (G-insulin) and be remembered for
hydrogels. Under hyperglycemic conditions, rivalry between G-insulin and glucose
prompts the arrival of G-insulin in a glucose-subordinate way. Wu and collaborators as of
late built up a MSN framework topped with Con A (Wu et.al, 2013). The framework is
involved Con A bound to a mannose moiety, which is utilized to top the pores of the MSN
which contain rhodamine as a model medication. The subsequent framework was both
pH and glucose-responsive. Activating of the framework by pH happens in light of the fact
that Con A exists as a dimer or monomer at low pH, and expect a tetrameric state at
unbiased pH. Aggressive authoritative of glucose with the topped Con A prompted an
arrival of the medication stacked inside the MSN. Without glucose or a pH trigger, no
medication discharge happened. (Wu et.al, 2013)

6.2 Glucose Oxidase GOx System

Glucose Oxidase (GOx) Systems Glucose oxidase is able to do enzymatically

catalyzing the oxidation of glucose to gluconic acid with high explicitness. The pace of
enzymatic generation of gluconic acid is identified with the nearby glucose fixation. A
commonplace shut circle framework using glucose oxidase is included a pH-delicate
polymer network containing both insulin and GOx. The framework experiences a physical
change, for example, hydrolysis or volume stage progress as the pH of the framework is
adjusted by gluconic corrosive generation, accordingly discharging the insulin ensnared
inside the grid in a glucose-subordinate fashion (Bratlie et.al, 2013) (Ravaine et.al, 2008)
Figure 3: Glucose sensitive nano network mechanism

Source: Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015 Jul; 7(4): 548–564.

Gu and collaborators as of late built up a glucose-sensitive nano-network for insulin

conveyance utilizing GOx as the glucose-detecting component as shown in the figure
above (Gu et.al, 2013). A two-fold emulsion strategy was utilized to get ready acetal
changed dextran (m-dextran) nanoparticles which included insulin, GOx, and catalase
(CAT). The nanoparticles were covered with either emphatically charged chitosan or
adversely charged alginate. The restricting surface charges caused the nanoparticles to
amass into a permeable 3D nano-arrange. The transformation of glucose to gluconic acid
set off the hydrolysis of the acetal gatherings to ethanol and CH2CO which brings about
the stage change of hydrophobic m-dextran to dextran, which is hydrophilic. This stage
change brings about the arrival of the entangled insulin in a glucose-responsive design.
The nano-organize engineering supplied the framework with adequate mechanical
solidarity to beat a burst discharge at the infusion site. Moreover, the permeable structure
prompted the nearness of microchannels which encouraged higher paces of glucose
dissemination through the nano-organize prompting close to zero-request compound
energy. The framework demonstrated no huge insulin discharge at ordinary glucose
levels (100 mg dL−1) however changed to quick insulin discharge under hyperglycemic
conditions (400 mg dL−1). In vivo examinations, a solitary subcutaneous infusion of the
nano-organize was equipped for keeping up a diabetic mouse's blood glucose levels in
the normoglycemic go for 10 days (Gu et.al, 2013).

6.3 The use of Phenylboronic Acid (PBA)

A detriment of protein-based glucose detecting is that environmental factors, for

example, pH and temperature must be firmly controlled to forestall protein denaturation.
The plausibility of denaturation constrains the glucose-detecting applications and sensor
lifetimes of protein-based frameworks. This postures difficulties for the long-haul
estimation of blood glucose by such sensors. An appealing option is the utilization of
Phenylboronic corrosive and its subsidiaries as the glucose-detecting moiety in both BGL
estimation and insulin conveyance applications. The capacity of Phenylboronic corrosive
to reversibly tie to polyols has been well established (Lorand et.al, 1957). This has
enabled Boronic corrosive subordinates to fill in as the recognition component in glucose-
responsive insulin conveyance and BGL estimation applications.

Phenylboronic corrosive in its impartial structure exists as a trigonal planar

hydrophobic particle however is deprotonated under somewhat fundamental conditions
(pKa> 8) where it exists as a tetrahedral hydrophilic atom with a net negative charge. The
balance between the two states is pushed towards the tetrahedral state within the sight
of diols and polyols, for example, those found in glucose (Kataoka et.al, 1998). This
balance can be used to trigger the disintegration of amphiphilic nanocarriers and along
these lines discharge insulin. The balance moves from the impartial to the charged
structure can likewise trigger the growth of crosslinked hydrogel grids.
 Kataoka et al. were the first to report an engineered glucose-responsive framework
for insulin conveyance in 1998 (Kataoka et.al, 1998). The gathering orchestrated a
polymer network of poly (N-isopropyl acrylamide) (PINPAAm) that included PBA as a
glucose-detecting moiety. Upon glucose complexation with the PBA, the hydrophilicity of
the grid expanded, making the framework swell and discharge insulin in a glucose-
responsive fashion. Since this underlying work, a few other insulin conveyance
frameworks have been formulated which use the PBA moiety for its glucose-detecting
properties (Gattas-Asfura, 2013).

7.0 Conclusion and Recommendation.

Researches on Diabetes Mellitus must focus on the three pillars of its treatment.
Nanotechnology has therefore proved significant tools in much precise data on diagnosis
on the glucose level including the automatic regulation and injection of insulin to help aid
the dysfunctional organ and cells in the body. It is therefore important to conduct a clinical
study on the actual people in assessing the efficacy of the method. Also, studies on its
side effects should also be conducted in order to avoid or minimize health risks that may
arise due to the use of the method.

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