ASSIGNMENT

DRUG DELIVERY THROUGH

NANOHYDROGELS

PRABHAT BIST
BMS IIIrd Year
XO-231
 DRUG DELIVERY SYSTEM

Drug Delivery System (DDS) defined as a formulation or a device that enables the introduction
of a therapeutic substance in the body and improves its efficacy and safety by controlling the
rate, time and place of release of drugs in the body.

Targeted Drug Delivery System:

 Targeted drug delivery system is a special form of drug delivery system where the drug is
selectively targeted or delivered only to its site of action or absorption and not to the non-
target organs or tissues or cells.
 It increases the concentration of the drug in some parts of the body relative to others
when administered in a person’s body.
 It improves efficacy and reduce side effects of the drug.

The Drug can be delivered to:

 Capillary bed of active sites.

 Specific type of cells. Ex: Tumor cells but not to normal cells.
 Specific organ (or) tissues.
Drug Carrier:

A drug carrier is any substrate used in the process of drug delivery which serves to improve the
selectivity, effectiveness, and/or safety of drug administration.

 Drug carriers achieve different goals: bioavailability, stability, preventing the drug
interactions.
 It is developed for various purposes depending on it needs and also, it describes unique
nature and applications.
 Drug Carrier types:

Microspheres

Microcapsules
Drug Carrier System

Nanoparticles

Aquasomes

Liposomes

Emulsions

Cellular Carriers

So, we are going to talk about Drug Delivery through Nanoparticles, more specifically,
Nanohydrogels.
 HYDROGELS

 Hydrogel has Hydrophilic polymeric networks made up of 3D chains which are water
insoluble.
 Hydrogels are natural or synthetic highly absorbent cross-linked polymers which are
capable of imbibing huge volumes of water so, that’s why they might contain around
99.9% of water.
 Chemical and physical crosslinks like crystallites or entanglements makes the
network insoluble and mainly two types of polymers are present; homopolymers and
copolymers.
 Their porosity and compatibility with aqueous environment allows them to swell in
aqueous media and makes them a good bio-compatible drug delivery vehicle.
 Also, the polymeric network contributes to its physical integrity and strength.

Classification of Hydrogels:

 Based on Structure:
1. Amorphous Hydrogels: macromolecular chains are arranged in a random
fashion.
2. Semi-Crystalline Hydrogels: are moderately water-swollen hydrogels containing
crystalline domains.
3. Hydrogen Bonded Hydrogels: Ex. PVDT-PAA - A hydrogen bonded and calcium
ion cross-linked hydrogel.
 Based on Charge:
1. Neutral Hydrogels: have no charge. Ex. Dextran, Agarose, Pullulan etc.
2. Anionic Hydrogels: have negative charges. Ex. Alginic acid etc.
3. Cationic Hydrogels: have positive charges. Ex. Chitosan etc.
4. Ampholyitc Hydrogels: have both negative and positive charges. Ex. Collagen,
Fibrin etc.
 Based on Method of Preparation:
1. Homopolymer Hydrogels: have polymer network derived from only one kind of
polymer as basic structural unit and may have cross-linked skeletal structure.
 2. Co-polymer Hydrogels: consists of two or more different type of monomers with
at least one hydrophilic component arranged randomly.
3. Multipolymer Hydrogels: aka Interpenetrating Polymeric Network (IPN): it
has a network of two independent cross-linked synthetic and/or natural polymer
component.
 Based on Mechanism of Drug Delivery:
1. Diffusion Controlled Release Systems: are of two types: uses reservoir or
matrix devices which allow diffusion-based drug release through a hydrogel
mesh or pores filled with water.
Reservoir devices: In this system, the hydrogel polymeric membrane is coated on
a drug-containing core which then produces capsules, spheres or slabs having a
high drug concentration in the very center of the system which facilitates a
constant drug-release rate. Drug release is constant and time independent unlike
the matrix system.
Matrix Devices: In Matrix system, the drug is uniformly distributed from the
overall structure of the hydrogel. Basically, the drug is released through the
macromolecular pores rather than from the core and it is time-dependent unlike in
reservoir system.

Schematic of diffusion controlled release systems: (a} reservoir device (b) matrix device
 2. Swelling Controlled Release Systems: In swelling controlled mechanism drug
diffusion is faster than hydrogel expansion. The drug being spread within a glassy
hydrogel polymer which begins to swell when in a contact with bio-fluid. The
swelling of the polymer is due to the lowering of transition temperature of the
polymer followed by relaxation of the macromolecular chains as entering of
penetrant in the glassy polymer. Here, the drug release from the hydrogel
significantly depends on the stretched volume of the device.

Phenomenon of swelling from a controlled release system

3. Chemically Controlled Release Systems: They are of two types:
Erodible DDS: The drug is released as the Hydrogel polymer gets degraded or
dissolute in the media.
Pendent Chain System: Here, the drug is released due to the degradation of the
linkages which links the drugs to the polymeric back bone.

Schematic of chemically controlled release systems

4. Environment Responsive systems: These drug systems (hydrogels) are
environmental sensitive and have the ability to respond to changes in their
external environment.
Whenever there is a change in pH or ionic strength of the surrounding biological
fluid or temperature the hydrogels experience a significant change in their
structure, swelling behavior, permeability or strength.
They are also known as Smart Hydrogels as they can revert back to their normal
state and shape after the response has been finished.
They are of many types but the main are:
pH Sensitive Hydrogels:
 It has a kind of composition of the gel which responds to the pH of
the surrounding environment by either shrinking or swelling
 These hydrogels contains acidic or basic side groups attached to their
backbone which may ionize according to change in pH of the surrounding
media; ionization occurs only when pH (environment) > pKa (ionizable
group).
 Which leads to increase in degree of ionization with number of fixed
charges and ultimately electrostatic repulsion between the chains is
increased.
 As a result, uptake of solvent is increased and swelling occurs.

Temperature Sensitive Hydrogels:

 Hydrogels which can Swell and Deswell in response towards the change
in temperature of the surrounding fluid are known as Thermo sensitive or
Temperature sensitive Hydrogels.
 They are extensively used in ON/OFF drugs release regulations,
biosensors and intelligent cell culture dishes.
 Can be classified as:
 Positive Hydrogels contracts upon cooling below the UCST (Upper
Critical Solution Temperature).
  Negative Hydrogels contracts upon heating above the LCST (Lower
Critical Solution temperature).

There are several other stimuli, other than pH and Temperature, like Light,
Electric Field, Magnetic Field, Ultrasound, Chemicals (Ionic Species) etc.
which can cause drug release from the depot.

NANOHYDROGELS
 These are the Hydrogels prepared in water by self-aggregation of polymers of natural
origin like Dextran, Pullulan or cholesterol containing polysaccharides.
 Swelling of cholesterol containing polysaccharides is done by stirring them at 50°C for
12h in an aqueous buffer.
 The Nanohydrogels are formed after sonication at 25°C for 10 mins.
 They are of nano dimensions usually i.e. 20-30 nm and mainly used for cell targeting and
basically are pH dependent. Ex. Adriamycin has been delivered to tumor cells via
nanohydrogels and the drug showed pH dependent release (Highest at pH below 6.8)
 These Nanohydrogels have been used for controlled release of proteins like lysozymes,
albumin, immunoglobulin etc.

Methods of Preparation of Hydrogels:

Crosslinking

Isostatic
Freeze
Ultra HIgh
Thawing
Pressure

Methods of
Preparation of
Hydrogels
Nucleophilic
Use of
Substituion
Irradiation
Reaction

Using
Gelling
Agents
 APPLICATION OF HYDROGELS:
1. DNA-HYDROGELS: with the development of Multi-functional Quantum Dot
(QD) DNA Hydrogels, an interesting application of Hydrogels has been made in
the field of Medical Biotechnology.
 They are composed of complementary strands of DNA hybridizes to form
cross-linked network that swells in an aqueous environment.
 Zhang et al. recently developed a QD-based DNA hydrogel having highly
tunable size, spectral and delivery properties.
 It binds to the DNA binding drug Doxorubicin which targets the Cancer
cells and also its potency got increased in vitro after binding to QD-DNA.
 Also, increased tumor accumulation in vitro, High Bio- compatibility,
almost threefold more efficacy has been seen in zinc sulphide QD
Doxorubicin DNA hydrogels which served as an excellent tool for in vivo
bio-imaging in monitoring tumor growth over time.
 Aptamers such as siRNA were used to target specific cell types to deliver
drugs specifically and modulate protein expression in various cell types.

(a) Schematic view of the synthesis process of the DNA functionalized QDs followed by the
formation of the QD hydrogel through hybridization with DNA. (b). Schematic view of the
modification process on the QD hydrogel for specific targeting of the cell using aptamer for drug
delivery
2. Peroral Drug Delivery:
 Drug administration via mouth has been the most common and patient
compliant method in pharmaceutical application of hydrogel.
 Hydrogel can deliver drugs to four major specific sites like mouth, stomach,
small intestine and colon although there are major barriers in peroral drug
administration like enzymes and pH change in Gastrointestinal system,
presence of bile salt and the Liver mediated First Pass Metabolism.
 To release the drug properly in the respective sites, Bio-adhesive
characteristics and Swelling behavior are controlled in the presence of
surrounding biological fluid.
 The drug concentration along with its absorption might increase locally due to
the adhering of drug to some specific regions in the oral pathway.

3. Drug Delivery in the G.I.T.:

 A drug can be designed to be delivered locally to some specific sites in the
Gastrointestinal Tract by Hydrogel based Devices Ex. polyionic complex
hydrogels of chitosan with ring-opened PVP which is used in Osteoporosis
therapy.
 Ex. The treatment of Peptic Ulcer disease caused by the bacteria H.pylori is
done by the use of some specific antibiotic drug delivery device.
 The main function of the hydrogel is to protect the drug in the harsh acidic
environment of the stomach before releasing the drug into the intestine.

4. Protein Drug Delivery:

 Hydrogels forms In situ network and releases protein slowly at the specific
sites.
 Ex. Interleukins are conventionally given as injection.
 Hydrogels are Biodegradable and biocompatible and has a better patient
compliance.
5. Tissue Engineering:
 Micronized Hydrogels also known as Microgels can be use to deliver
macromolecules like Phagosomes into Cytoplasm of APC (Antigen Presenting
Cells)
 Hydrogels molds themselves to the pattern of membranes of the tissues due to
acidic conditions and have sufficient mechanical strength, so basically they
are pH-Dependent Hydrogels.
 ADVANTAGES OF HYDROGELS DISADVANTAGES OF HYDROGELS

Flexible just like that of natural tissue due As they are non-adherent so, there might
to considerable amount of water content. be a need of secondary dressing to secure
them.
They can be injected and are They have low mechanical strength.
Biocompatible.
Environment sensitive hydrogels are very Conditions like dehydration, hypoxia, and
important and useful as they can release lens disposition can be caused by wearing
the drugs in response to change in pH, lens made up of Hydrogels.
Temperature etc.
Release of drugs, growth factors, nutrients They are very expensive.
etc. can be scheduled/timed by using
hydrogels which guarantees a proper
growth of the target region.
Hydrogel entrapping the microbial cells They are difficult in handling and loading.
leads to chances of low toxicity.
They are easy to Modify During surgical device implantation and
retrieval, there are some risks associated
with them.

REFERENCES:

 Sri. M, Bindu & Vadithya, Ashok & Chatterjee, Arkendu. (2012). As A Review on
Hydrogels as Drug Delivery in the Pharmaceutical Field. INTERNATIONAL
JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES. 1. 642-661.
 Narayanaswamy R, Torchilin VP. Hydrogels and Their Applications in Targeted
Drug Delivery. Molecules. 2019 Feb 8;24(3):603. doi: 10.3390/molecules24030603.
PubMed PMID: 30744011; PubMed Central PMCID: PMC6384686.
 Amin, Saima & Rajabnezhad, Saeid & Kohli, Kanchan. (2009). Hydrogels as
potential drug delivery systems. Scientific research and assay. 3. 1175-1183.
 Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater.
2016 Dec;1(12):16071. doi: 10.1038/natrevmats.2016.71. Epub 2016 Oct 18. PubMed
PMID: 29657852; PubMed Central PMCID: PMC5898614.