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Nanogel
1. L/O/G/O
By: Mariam Abd El Aziz Zewail
MS.C Faculty of pharmacy Damanhur university
2/3/2019 1
2. o What are nanogel?
o Properties of nanoogels.
o Advantages and disadvantages of hydrogels.
o Synthesis of hydrogels.
o Drug loading and release from nanogels.
o Characterization of hydrogels.
o Applications of hydrogels.
o Current status in clinical trials and marketed
formulations.
o Summary and future prospectus.
o References.
2/3/2019 2
3. • Sudden outbreak in the field of nanotechnology
have introduced the need for developing nano-
systems which proven their potential to deliver
drugs in controlled, sustained and targetable
manner.
• With the emerging field of polymer sciences it has
now become inevitable to prepare smart nano-
systems which can prove effective for treatment as
well as clinical trials progress.
2/3/2019 3
4. What are nanogels?
A Hydrogels are
three dimentional
network structures
obtained from
polymers which can
absorb and retain
big amount of water,
so they are
biocompatible.
A gel is a colloidal
system formed by
continuous solid
phase dispersed in
fluid phase. If this
fluid is water, the
gel is hydrogel.
Nanogels are
nanosized
hydrogels, in
tens to hundred
nanometers in
diameter.2/3/2019 4
7. Respond to environmental changes.
Biocompatibility and biodegradibility.
Reaching small capillaries, penetrate tissues
through paracellular and transcellular pathway.
Controlled and sustained drug delivery.
Avoid rapid phagocytic clearance.
Ability to encapsulate a variety of compounds
2/3/2019 7
Advantages and limitations of nanogels
10. 2/3/2019 10
Nanogels typically range in size of 20–200 nm
in diameter and hence are effective in avoiding
the rapid renal exclusion but are small enough
to avoid the uptake by the RES.
Good permeation capabilities due to extreme
small size, can cross the BBB.
ASize
11. The extent of swelling capacity and driving forces of
nanogels/microgels are the same as their bulk or
macrogels, but the most beneficial feature is their
rapid swelling/de-swelling characteristics.
2/3/2019 11
B
Swelling
15. 2/3/2019 15
Environmental
parameters
Temperature
120 nm
400 nm
The polymer–solvent interactions
decreases upon increasing
temperature above the LCST (32 ◦C for
PNIPAAm) due to the dominating
effect of hydrophobic interactions at
an elevated temperature.
16. 2/3/2019 16
Environmental
parameters Ionic
strength
At high ionic strength, the
swelling of cationic PAETMAC
nanogels is governed by the
concentration of the cross-
linker, while at low ionic
strength the swelling is
influenced by both the cross-
linker and the concentration
of the charge.
17. N,N-methlylenebisacrylamide (MBA) is the most widely
used cross-linker due to its high reactivity.
The cross-linker concentration results in a various range
of products with different cross-linked dense networks
of various nanometer size and distribution.
2/3/2019 17
Nanogel
structure Amount of cross
linker
Cross linker
concentration
Swelling
Degree
18. 2/3/2019 18
Nanogel
structure Charge
density
Ionized groups attract hydrated counterions
This favors the swelling of the gel, while the entropy
elasticity of the polymer chains opposes the expansion
The ionization of weak polyelectrolyte gels
depends on the pH value
Reduction in the total charge and number of counterions as
the pH changes results in compression of the gel until the
excluded volume of the polymer chains limits further
compression.
19. In general drug loading from nanogels is higher
compared to other nanosized carriers like liposomes,
micelles and nanoparticles.
2/3/2019 19
CHigh loading capacity
Nanogels are highly swollen and can incorporate 30% wt.
and more drug molecules through covalent or electrostatic
bonding with the nanogel chains.
Nanogels do not have a dense core or a defined
surface and can undergo dramatic volume transitions
upon environmental changes.
20. PNIPAM-based nanogels do not cause any change in
nanogel size even after 4 months of storage at 4◦C
Nanogels or polymeric micellar nanogel systems have better
stability over the surfactant micelles and exhibit lower critical
micelle concentrations, slower rates of dissociation, and
longer retention of loaded drugs.
2/3/2019 20
DStability
22. Classification of nanogels
Response
to stimuli
Responsive
Non-
responsive
Method of
preparation
Physically
cross
linked
Chemically
cross
linked
2/3/2019 22
sol – gel reversibility by an
external stimulus
23. According to the method of preparation they can be
further classified into
Nanogels
Physically
cross-linked
Hydrogen
bond
Hydrophobic
interactions
Electrostatic
interactions
Chemically
cross-linked
Amine based
cross linking
Disulfide
based cross
linking
Photo
induced cross
linking
2/3/2019 23
27. Bulk polymerization.
Because of the auto-acceleration effect in the polymer reaction, the
viscosity of the reaction mixture increases and it may not be possible
to control the formation of macrogelation
product
2/3/2019 27
Conversion of Macroscopic Gels to Nanogels
28. Disadvantages:
This is a time- and energy-consuming process and results
in significant loss of material.
Nevertheless, micro- and nanogels obtained from this method have
particles of different shape and sizes.2/3/2019 28
29. 2/3/2019 29
Methods of nanogel preparation
Photolithographic techniques.
Micromolding method.
Water in oil heterogenous emulsion methods.
Reverse micellar method
Heterogeneous free radical polymerization
Inverse (mini) emulsion polymerization.
Membrane emulsification
Carbodiimide coupling .
Precipitation polymerization.
Dispersion polymerization.
Addition fragmentation transfer (RAFT) process
31. Novel pullulan chemistry modificationPhysical
self assembly
cholesterol
Reacting mixture of cholesterol isocynate in
dimethyl sulfoxide and pyridine.
Pullulan was substituted with 1.4 cholesterol
moieties per 100 anhydrous glucoside units.
The preparation was freeze dried and in aqueous
phase it formed nanogel which was complexed
with W-9 peptide for delivery in osteological
disorders.
2/3/2019 31
34. Size of the prepared nanoogel particles can be controlled by
amount of surfactants and crosslinking agents as well as stirring
speed during the formation of inverse emulsion.
Cross
linking Inverse (mini) emulsion method
2/3/2019 34
Aqueous
polymer Oil phase
High speed
stirrer
Or
homogenizaer
Cross linker
Cross linked
particles are
dispersed in
organic solvent
Purification
Lyophilization
37. Loading nanogels with drugs
Both hydrophilic and lipophilic low molecular weight drugs
(e.g. certain chemotherapeutics and macromolecular
therapeutics (DNA,siRNA, peptides and proteins may
become incorporated into the nanogel network.
2/3/2019 37
Physical
Entrapment
Covalent
conjugation
39. 1- Steric entrapment
2/3/2019 39
Physical
entrapment
Compounds are present in the polymer
solution during the gelation process.
When the dimensions of the encapsulated
therapeutics exceed the mesh size of the
nanogel network, their diffusional leaching can
be prevented
Advantage:
Encapsulation
macromolecular
therapeutics.
Disadvantage:
Polymerization may
occur under conditions
that are possibly
detrimental for the
therapeutic cargo.
40. Physical
entrapment
2/3/2019 40
• Cholesterol-modified pullulan nanogels can be used
for protein encapsulation.
• The main driving force for protein encapsulation is
the hydrophobic attraction between the cholesteryl
moieties in the nanogels and hydrophobic
nanodomains in the protein of interest.
2- Hydrophobic interactions
Disadvantage:
Relatively low degrees of loading.
41. 2/3/2019 41
Physical
entrapment 3- Electrostatic interactions
Incorporation of therapeutics in charged nanogels
is based on electrostatic interactions between the
biological agent and the ionized polymer matrix.
42. 2/3/2019 42
Physical
entrapment 3- Electrostatic interactions
Incorporation of therapeutics in charged nanogels
is based on electrostatic interactions between the
biological agent and the ionized polymer matrix.
Cross-linked gel
comprised of
neutral PEG and
anionic PAA
polymer chains
Solution of a cationic
protein cytochrome c0
43. For example, enzymes modified with acrylic
groups were copolymerized with acrylamide
either during nanogel preparation.
2/3/2019 43
Covalent
conjugation
Disadvantage:
Covalent attachment is not feasible for every type of drug or
application as it may also alter the drugs’ effectiveness.
Covalent conjugation of biological agents
can be achieved using preformed
nanogels or during nanogel synthesis.
51. Optimizing nanogel architecture for in vivo
application
The hydrophilic modification of nanoparticles can
Prevent uptake by mononuclear phagocytic
cells.
1.
Decrease the recognition by the immune system2.
Enhance their circulation time in the bloodstream.3.
2/3/2019 51
52. With regard to the shielding of nanogels, most
research is focused on PEGylation.
PEGylation refers to the modification of a particle
surface by covalently grafting, entrapping or
adsorbing polyethylene glycol (PEG).
Nanogels contained relatively short PEG chains (1
kDa) cleared relatively rapidly from the blood (t1/2
=17 min) and accumulated in the liver, while the
optimal coating for long-circulating nanoparticles
would have PEG between 2 and 5 kDa.
52
Shielding nanogel surface by
hydrophilic shell
55. Ocular drug delivery
2/3/2019 55
Nanogel was used to encapsulate pilocarpine in order to
maintain an adequate concentration of the pilocarpine at the
site of action for prolonged period of time.
pH-sensitive polyvinyl pyrrolidone-poly (acrylic acid)) nanogels
prepared by γ radiation-induced polymerization.
56. 2/3/2019 56
pH-sensitive polyvinyl pyrrolidone-poly (acrylic
acid) (PVP/PAAc) nanogels prepared by γ
radiation- induced polymerization of acrylic acid
(AAc) in an aqueous solution of polyvinyl
pyrrolidone (PVP) as a template polymer were
used to encapsulate pilocarpine in order to
maintain an adequate concentration of the
pilocarpine at the site of action for prolonged
period of time.
57. Nanogels for proteins and peptide
delivery
Nanogel can interact strongly with proteins than
liposomes or amphiphilic peptide carriers, as they can
form stable suitably sized complex capable for
intracellular uptake with proteins.
Loading of proteins into the nanogels has got lot of
advantages owing to the increased surface area-to-
volume ratio attributed by nanosizing, controllable
physical and chemical properties, and high loading
capacity.
2/3/2019 57
CHP loaded with a peptide drug W9 with an aim to
increase its stability.
CHP by forming a complex with W9 was reported to
prevent its in vitro aggregation and increases its
stability.
In vivo animal studies using a murine model for bone
resorption demonstrated that the injection of nanogels
at dose of 24mg/kg twice daily for 7 days caused
significant inhibition ofbone mineral density reduction,
where as W9 in same dose does not induce any such
inhibition.
58. Nanogels in Topical and Transdermal
Drug Delivery
2/3/2019
Prolonged residence time offered by nanogel system
increases the drug concentration at the application
site when compared with conventional gels or
creams. 58
59. The curcumin loaded nanogels showed a four fold
increase in steady-state transdermal lux of curcumin
as compared with that of control curcumin solution.
2/3/2019 59
Upper skin
Middle skin
Lower skin
61. Immunological applications
2/3/2019 61
Antigen-specific immune responses are the
principle behind vaccination.
For an effective vaccination, the administered
antigen must be targeted to antigen-presenting
cells so as to obtain the desired immune responses.
Polymeric nanogels are an effective carrier for
vaccines with the ability to deliver the targeted
antigen.
Nanogels were loaded with peptide, proteins, DNA
and RNA based vaccines.
62. Immunological applications
2/3/2019 62
Antigen-specific immune responses are the
principle behind vaccination.
For an effective vaccination, the administered
antigen must be targeted to antigen-presenting
cells so as to obtain the desired immune responses.
Polymeric nanogels are an effective carrier for
vaccines with the ability to deliver the targeted
antigen.
Nanogels were loaded with peptide, proteins, DNA
and RNA based vaccines.
A nanogel loaded with Clostridium botulinum
type A neurotoxin for intranasal delivery as
vaccine for the treatment of mucosal infection
using CHP was developed.
The nanogels were reported to adhere effectively
to the nasal epithelium, and the attached antigen
was effectively taken up by nasal mucosal
dendritic cells. Increased production of botulinum
toxin-neutralizing IgG and IgA antibodies indicated
the effective vaccination using this system.
63. Current status in clinical trials and
marketed formulations.
2/3/2019 63
64. Current status in clinical trials
2/3/2019 64
Clinical trial of Cholesteryl pullulan (CHP)
nanogels has shown tremendous potential in
delivering peptides.
The CHP-HER-2 vaccine was administered to
nine patients biweekly dosing of 300μg with
booster doses. The vaccine was well tolerated
with some skin sensitivity at site of
subcutaneous injection. All the patients showed
CD4+ and CD8+ T- cell response suggesting better
therapeutic activity.
65. Marketed formulations
NANOGEL® bone substitute comes in the form of
an apatite gel designed to replace bone with an
osteoconductive material.
NANOGEL® is a material designed to fill bone
defects that are not intrinsic to bone stability.
It is simple to place NANOGEL® percutaneously,
enabling the surgeon to use it in closed site filling
indications.
NANOGEL® is gradually resorbed and replaced
by bone during the remodelling process.
Hydroxyapatite nanoparticles gel
2/3/2019 65
67. • Nanogels are a distinct class of drug carriers with
promising properties for encapsulating small
molecules and peptides as well.
• They have numerous advantages due to ease of
formulation, biocompatibility and high loading
capacity.
• Nanogels are highly swollen and can incorporate
30% wt. and more drug molecules through covalent
or electrostatic bonding with the nanogel chains.
• Nanogels surface can be modified with different
ligands to optimize their in vivo delivery.
2/3/2019 67
68. • The field of nanogels applications is rapidly
growing and receiving considerable attention.
• Nanogels needs further studies concerning their
toxicity, immunogenicity, pharmacokinetics and
pharmacodynamics.
• Research should be focused on improving nanogel
properties to suit different biomedical and clinical
applications.
2/3/2019 68
70. • Kabanov AV, Vinogradov SV. Nanogels as pharmaceutical carriers: finite
networks of infinite capabilities. Angewandte Chemie International Edition.
2009;48(30):5418-29.
• Sultana F, Manirujjaman M, Imran-Ul-Haque MA, Sharmin S. An Overview
of Nanogel Drug Delivery System. Journal of Applied Pharmaceutical
Science Vol. 2013;3(8 Suppl 1):S95-S105.
• Sivaram AJ, Rajitha P, Maya S, Jayakumar R, Sabitha M. Nanogels for
delivery, imaging and therapy. Wiley Interdisciplinary Reviews:
Nanomedicine and Nanobiotechnology. 2015.
• Sasaki Y, Akiyoshi K. Nanogel engineering for new nanobiomaterials: from
chaperoning engineering to biomedical applications. The Chemical Record.
2010;10(6):366-76.
• Oh JK, Drumright R, Siegwart DJ, Matyjaszewski K. The development of
microgels/nanogels for drug delivery applications. Progress in Polymer
Science. 2008;33(4):448-77.
• Akiyoshi K, Deguchi S, Moriguchi N, Yamaguchi S, Sunamoto J. Self-
aggregates of hydrophobized polysaccharides in water. Formation and
characteristics of nanoparticles. Macromolecules. 1993;26(12):3062-8.
• Dorwal D. Nanogels as novel and versatile pharmaceuticals. Int J Pharm
Pharm Sci. 2012;4(3):67-74.
2/3/2019 70
71. 2/3/2019 71
• Singh N, Lyon LA. Au nanoparticle templated synthesis of pNIPAm nanogels. Chemistry
of materials. 2007;19(4):719-26.
• Akiyoshi K, Kobayashi S, Shichibe S, Mix D, Baudys M, Kim SW, et al. Self-assembled
hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs:
complexation and stabilization of insulin. Journal of Controlled Release. 1998;54(3):313-
20.
• Missirlis D, Kawamura R, Tirelli N, Hubbell JA. Doxorubicin encapsulation and diffusional
release from stable, polymeric, hydrogel nanoparticles. European journal of
pharmaceutical sciences. 2006;29(2):120-9.
• Amamoto Y, Otsuka H, Takahara A. Synthesis and Characterization of Polymeric
Nanogels. Nanotechnologies for the Life Sciences. 2011.
• Raemdonck K, Demeester J, De Smedt S. Advanced nanogel engineering for drug
delivery. Soft Matter. 2009;5(4):707-15.
• Nukolova NV, Oberoi HS, Cohen SM, Kabanov AV, Bronich TK. Folate-decorated
nanogels for targeted therapy of ovarian cancer. Biomaterials. 2011;32(23):5417-26.
• Kim H-J, Zhang K, Moore L, Ho D. Diamond nanogel-embedded contact lenses mediate
lysozyme-dependent therapeutic release. ACS nano. 2014;8(3):2998-3005.
• Mangalathillam S, Rejinold NS, Nair A, Lakshmanan V-K, Nair SV, Jayakumar R.
Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route.
Nanoscale. 2012;4(1):239-50.
• Smith DM, Simon JK, Baker Jr JR. Applications of nanotechnology for immunology.
Nature Reviews Immunology. 2013;13(8):592-605.
• Ferreira SA, Gama FM, Vilanova M. Polymeric nanogels as vaccine delivery systems.
Nanomedicine: Nanotechnology, Biology and Medicine. 2013;9(2):159-73.
