3. INTRODUCTION
The concept of stimuli-responsive drug delivery was first suggested in
the late 1970s with the use of thermosensitive liposomes for the local
release of drugs through hyperthermia
SRDDS are capable of adjusting drug release rates in response to a
physiological need and manipulate the drug release by sensing
changes
A new class of polymers were discovered which respond to their
environment by changing their physical and chemical properties
Change is reversible in nature
Since such systems are capable of releasing drug in repsonse to
stimuli, they are often called as smart or intelligent DDS
1
5. Advantages
Maintain single dose drug in therapeutic range
Targeted delivery of drug
Effective for rapidly destroyed drug
They are also used to control the release (sustain release) and to increase the
retention time at the application site
Improved patient compliance
2
6. Classification
• Information about the controlled variable is
not automatically detected
• Triggered by external stimuli such as
temperture, ultrasound, electric current, etc.
EXTERNALLY REGULATED
(OPEN LOOP SYSTEM)
• Information about the controlled variable is
detected and system output is adjusted
• Stimulus is produced without any external
intervention
• Approaches like chemical and biological are
used
SELF REGULATED
(CLOSED LOOP SYSTEM)
4
8. PULSATILE DRUG DELIVERY SYSTEM
PDDS delivers the right dose at the specific time at specific area
It is defined as release of required amount of drug within a short
time period immediately after a predetermined off-release period,
i.e. lag time
Drug release is programmed by external stimuli such as
magnetism , ultrasound, electrical effect, irradiation etc.
6
9. 1. THERMALLY REGULATED SYSTEM
Ideally, thermosensitive nanocarriers should retain their load at body
temperature (~37 °C), and rapidly deliver the drug within a locally heated
tumour (~40–42 °C) to counteract rapid blood-passage time and washout
from the tumour
In vivo, heat is generally applied by using temperature-controlled water
sacks, radiofrequency oscillators or miniature annular-phased array
microwave applicators
Thermo sensitive hydrogels used that show significant swelling changes
in water in response to temperature, Change in temperature affects
hydrogen bonding which in true, affects swelling and phase transition
happens 7
10. Thermo-responsive materials undergo a phase change below or above a
particular temperature
These changes are referred to as lower or upper critical solution
temperature (LCST or UCST) respectively
Such materials are insoluble above or below the critical temperature or
transform to a completely soluble form upon crossing the transition
temperature
Example: Thermosensitive liposomes (TSLs) are perhaps the most
advanced thermo responsive nanosystems, as shown by their use in
several clinical trials. Doxorubicin loaded TSLs (ThermoDox, Celsion
Corporation), in association with hyperthermia or radiofrequency
ablation, are at present being investigated in phase II trials 8
11. Negative thermosensitive polymers contract above their LCST
Positive thermosensitive polymers contract below their UCST
Poly N-isopropyl acrylamide (NIPAAM) is the most preferred
thermosensitive polymer used because of its lower LCST
9
13. 2. MAGNETICALLY MODULATED SYSTEM
Drug and magnetic beads are uniformly dispersed inside semi elastic
polymer matrix made of a nonbiodegradable polymer ethylene-vinyl acetate
copolymer (EV Ac)
Drug release follow matrix diffusion control in dissolusion medium
When the device is placed in a magnetic field, the magnetic beads
attempt to a align with the applied magnetic field including slight
rearrangement of the elastic polymer
Compression and expansion of polymer creates pore through which drug
release
11
14. These systems also induce hyperthermia at specific
site and help in drug release
Example: Magnetic nanopaticles such as
superparamagnetic iron oxide nanoparticles (SPIONs)
are incorporated into polymeric, lipidic, or protein
delivery systems to impart them with magnetic
properties
In an investigation, SPIONs coated with the thermo-
responsive polymer PNIPAAm and loaded with DOX
showed a rapid drug release above the lower critical
solution temperature (LCST)
Reason : Magnetic field induces hyperthermia and
hence a rapid release above the LCST.
12
16. 3. ELECTRICALLY REGULATED SYSTEM
These systems exhibits drug release under the effect of an applied electric field. Due
to action of a weak applied electric field (about 1V) on rate limiting membrane or
directly on the solute there by controlling its transport across the membrane.
Nanoparticles based on polypyrrole exhibited tailored drug-release profiles as a
result of a electrochemical reduction–oxidation and electric-field-driven movement
of charged molecules.
Electroporation — the application of a (typically high) transmembrane voltage to
cause the formation of pores in cell membranes and thus increase their permeability
to drugs.
Iontophoresis uses an electric field to enhance the transdermal delivery of charged
compounds such as PLGA nanoparticles loaded with estradiol and liposome-
containing insulin. 14
17. Case Study
Ge, et al. prepared dodecyltrimethylammonium bromide (DTAB) micelles
with decyl alcohol as a cosurfactant, and polypyrrole (PPy) was polymerized
in the hydrophobic core.
These nanoparticles were then loaded with a thermo-sensitive PLGA-PEG-
PLGA block polymer that showed temperature-dependent sol-gel
transformation. The polymer exists as a solution at 4 °C but rapidly forms a
gel at a physiological temperature of 37 °C .
Daunorubicin and fluorescein were loaded into the nanoparticles that were
embedded in the polymer matrix. The resulting material maintained its solid
hydrogel form at body temperature and demonstrated an electric-pulse
dependent drug release.
In the control group, the absence of an external stimulus resulted in
insignificant release of the cargo
15
19. 4. ULTRA SOUND REGULATED SYSTEM
Drug uniformly distributed inside a polymer
Ultrasonic field is applied externally to active drug release
The use of ultrasounds is also appealing because of their non-invasiveness,
the absence of ionizing radiations, and the facile regulation of tissue
penetration depth by tuning frequency, duty cycles and time of exposure
17
20. Ultrasound energy mediates drug release from a delivery vector by three
main mechanisms:
Heat generation
Acoustic cavitation
Acoustic radiation forces
18
21. • Microbubbles or other ultrasound contrast agents,
which are able to efficiently interact with ultrasonic
waves, have been used at diagnostic frequencies to
reduce the threshold required for cavitation.
• However, short lifespan and absence of extravasation
may still limit the use of microbubbles for tissue
targeting.
• This difficulty has been overcome by the development
of perfluorocarbon (PFC) nano emulsions that convert
into microbubbles under the action of therapeutic
ultrasounds.
• The bubbles are formed through acoustic droplet
vaporization and are subjected to cavitation, thus
promoting cellular uptake and/or release of the
entrapped drugs in the tumour site 19
22. 5. PHOTORESPONSIVE SYSTEM
Photoresponsive polymers change their physical or chemical
characteristics reversibly upon exposure to photoradiation
Azobenzene, o-nitrobenzene, coumarin, and pyrene derivatives are
routinely used for devising light-responsive drug delivery vectors
The different strategies available rely on either a one time or repeatable
on–off drug-release event triggered by photo sensitiveness induced
structural modifications of the polymers
For instance, the ultraviolet–visible reversible photoisomerization of the
azobenzene group (and its derivatives) — from trans to cis on
irradiation at 300–380 nm, and from cis to trans by shining light in the
visible region — enables photoregulated control of drug release
20
23. • The major drawback of light-triggered drug delivery is the low
penetration depth (~10 mm) that results from the strong scattering
properties of soft tissues in the ultraviolet–visible region of the spectrum
(less than 700 nm).
• Conventional light-induced drug delivery is thus only applicable to
regions of the body that can be directly illuminated (such as the eye or the
skin).
• However, by using photosensitive groups that respond to higher
wavelengths or exploiting two-photon technology, it is possible to replace
the ultraviolet–visible light source by a NIR laser (700–1,000 nm range)
with deeper tissue penetration, lower scattering properties and minimal
harm to tissues.
21
25. 6. PULSATILE DELIVERY BY OSMOSIS
Osmotically active agent such as water soluble salt is placed inside a rigid semi-
permeable housing, which is separated from the drug compartment by a movable
partition
The semi permeable membrane draws water inside by osmosis, leading to an
increase in volume which in turns produces pressure on the movable partition
The partition pushes the drug out of the compartment through a delivery
orifice
Thus, the drug delivery rate is controlled by the mass movement of water across
the permeable membrane
22
26. SELF REGULATED STIMULI RESPONSIVE
DRUG DELIVERY
Responsive system
System utilizing enzymes
System utilizing antibodies
Chelation system
23
28. 1.REDOX-RESPONSIVE SYSTEMS
Vitamin C (ascorbic acid), vitamin E and glutathione (GSH) are the reductive
substances that widely exist in the human body
Tumors exhibit characteristic oxidizing extracellular and reducing
intracellular environments generating a redox potential that has become the
driving force for the development of redox-responsive delivery vectors
Redox-responsive systems tend to lose their structural integrity in response to
the significantly higher cytosolic and nucleus concentration of glutathione
tripeptide (2–10 mM) compared to the extracellular matrix (2–20 μM).
Disulfide bonds (S–S) are the most studied redox-sensitive linkage used to
develop polymer-lipid or protein-based delivery systems. 25
30. Xiao and colleagues investigated a redox system approach.
Silica NPs were conjugated with a chemo- therapy agent (DOX) through an
amphiphilic peptide containing a disulfide bond. This drug carrier was able
to tightly entrap DOX with almost no leakage in the blood circulation and
healthy tissues
Additionally, the payload was only released when exposed to elevated GSH
in cancer cells. Rapid and sufficient drug release was observed intracellularly
when the disulfide bond between the nanocarrier and the drug was cleaved
by GSH
This redox system relied on significant differences in GSH levels among the
cancer cell matrix, extracellular matrix as well as normal cell matrix, leading
to lower toxicity and enhanced cancer cell specificity.
27
31. 2. ENZYME-RESPONSIVE SYSTEMS
Proteases are an integral part of tumor physiology. Cancer-associated
proteases (CAPs) such as matrix metalloproteinases (MMPs), cathepsin,
and urokinase plasminogen activators (uPAs) play a crucial role in
tumor tissue remodeling and in disease progression, invasion, and
dissemination
MMPs have been shown to be overexpressed in a majority of cancers
and are generally accepted to be important contributors to cancer
progression and invasiveness
As a result, enzyme-responsive vectors have been designed with an
enzyme-specific peptide in order to trigger delivery when the substrate
is degraded by the enzymatic activity within the tumors
28
32. Case studies
Duan et al. Designed a biodegradable amphiphilic block N-(2-
hydroxypropyl) methacrylamide (HPMA)
copolymer-gemcitabine (GEM) conjugate-based
nanoscale and stimuli-sensitive drug delivery
vehicle.
An enzyme-sensitive oligopeptide sequence Glycyl
phenyl alanyl leucyl glycine (GFLG) was
introduced to the main chain
It was demonstrated that the
conjugate-based
nanoparticles could accumulate
and be retained within tumors,
resulting in significant
increased antitumor efficacy
compared to free GEM
Cai et al. Cisplatin conjugated to a protease cleavable
peptide CGLDD was further bound to a PEG-
diacrylate hydrogel
This approach resulted in
prompt drug release in
response to the presence of
MMP-2 or MMP-9
29
33. 3. pH RESPONSIVE SYSTEM
The pH in the extracellular and inflammatory tissues of tumor is about 6.5, but
the pH of normal tissues is about 7.4. The pH of cytoplasm or organelles can be
even lower, such as endosomes (pH～5-6), lysosomes (pH～4-5) and Golgi
complex (pH～6.4).
In summary, the pH gradient between tumor and normal tissues provides a
good platform for designing the stimuli-responsive drug release system.
Polymers containing weakly acidic or basic side groups ionize alkaline or
acidic pH respectively. It donates or accepts H+ in respect to change in
environment.
Example: Poly acrylate polymer
Poly methacrylic acid (PMAA)
Poly L- Lysine
Poly ethylene imine
30
34. According to the changes of pH gradient within and outside the cells,
the construction strategies of the delivery systems mainly include the
following two categories:
i. Changes of conformation or dissolution behaviors of the polymer
under different pH conditions
ii.Delivery systems may disintegrate because of the fracture of acid-
sensitive groups in the nanocarriers, resulting in targeted delivery on
specific sites
31
35. Polymer
Changes in pH
Ionization of the gel
forming polymer Water
uptake
Swelling
Generation of
molecular pore
Release of
drug 32
37. 4. INFLAMMATION RESPONSIVE SYSTEM
It is based on the biodegradable hydrogels of cross-linked hyaluronic
acid
This approach is used to treat patients with inflammatory diseases like
rheumatoid arthritis using anti-inflammatory drug. This approach
involves dispersion of drug loaded lipid microspheres in to degradable
matrices of cross linked hyaluronic acid
Hyaluronic Acid gel is injected at inflammatory sites which are
specifically degraded by hydroxyl radicals produced from
inflammation-responsive cells during inflammation. Hyaluronic acid is
a linear mucopolysaccharide composed of repeating disaccharide
subunits of N-acetyl-D-glucosamine and D-gluconic acid
34
38. Hyaluronic acid has been extensively used in vivo as a therapeutic
agent for ophthalmic surgery and arthritis. In the living body,
hyaluronic acid is known to be degraded by two mechanisms:
(1) hyaluronidase as a specific enzyme
(2) hydroxyl radicals as a source of active oxygen
The degradation of hyaluronic acid by hydroxyl radicals may be
dominant and rapid as compared to that by hyaluronidase if
hyaluronic acid is injected in the proximity of inflammatory
reactions
35
41. 1.UREA RESPONSIVE SYSTEMS
The proposed system is based on conversion of urea into NH4HCO3
and NH4OH by the action of urease, this leads to increase in pH that
lead to changes in polymer erosion rates
A partially esterified copolymer of methyl vinyl ether and maleic
anhydride developed that displayed a pH dependent drug release. This
polymer dissolves by ionization of the carboxylic groups
38
Urea Urease NH4HCO3 + NH4OH
pH Ionization of polymer
Polymer erosion
42. This pH sensitive polymer containing dispersed hydrocortisone is
surrounded with urease immobilised in a hydrogel prepared by cross-linking
of a mixture of urease and bovine serum albumin with gluteraldehyde
Diffusion of urea into the hydrogel and its subsequent interaction with the
enzyme leads to a pH increase thereby enhancing erosion of the pH sensitive
polymer with concomitant release of hydrocortisone
39
Case Study
43. 2. GLUCOSE RESPONSIVE INSULIN DELIVERY
This system includes pH sensitive hydrogel containing glucose oxidase
immobilized in the hydrogel encapsulating saturated insulin solution
When glucose concentration in the blood increases glucose oxidase converts
glucose into gluconic acid which lowers the pH of the system
This induces swelling of the polymer which results in insulin release
40
44. System using a porous cellulose membrane with surface grafted poly
(acrylic acid) as a pH sensitive membrane
On immobilization of glucose oxidase onto the poly(acrylic acid) grafted
cellulose membrane, it becomes responsive to glucose concentration.
Basically in absence of glucose, the chains of poly(acrylic acid) grafts are
rod like, that reduce the porosity of the membrane and suppress insulin
permeation, however in the presence of glucose, gluconic acid produced by
glucose oxidase (GOD) promotes the poly(acrylic acid), making the graft
chains coil like and opening the pores to enhance insulin permeation and
release
41
Case Study
45. SYSTEM UTILIZING ANTIBODY INTERACTION
These systems are based on the principle that in the absence of free antigen the hydrogel
remains shrunk due to the intra-chain antigen-antibody binding in the polymer network,
while in the presence of the free antigen it swells because of dissociation of the intra-chain
binding by exchange of the grafted antigen for free antigen
This swelling/shrinking process was shown to be reversible
This approach has proposed antibody mediated release of contraceptive agent. The β subunit
of Human Chronic Gonadotropin (HCG) is grafted on to the surface of the polymer, which
in turn is exposed to antibodies to β –HCG
The appearance of HCG in the blood (indication of pregnancy) will cause release of
contraceptive drug as HCG competes for the polymer bound antibodies to HCG and initiates
the drug release
42
46. SYSTEM UTILIZING CHELATION
These include some antibodies chelates used for treatment of metal
poisoning.
The concept is based on the property of metals to accelerate the
hydrolysis of carboxylate or phosphate esters and amides
Tagging of the chelator to a polymer chain by a covalent ester or amide
link prevents its premature loss by excretion and reduces its toxic
effects.
In the presence of specific ion, the bound chelating agent forms a
complex followed by metal accelerated hydrolysis and subsequent
elimination of the metal chelate. 43
48. Contd….
Stimuli-responsive drug delivery systems using a change in pH,
redox potential, enzyme concentration, as well as temperature and
magnetism as a source of stimulation.
Although these kinds of endogenous or exogenous stimulus can
serve as independent incentives, they are often used in
combination to obtain greater specificity and flexibility.
Multistimuli drug delivery systems include examples of pH-redox,
photo-magnetic, thermo-redox combinations, and others
Bistimuli and tristimuli systems have been developed for efficient
drug delivery 45
49. Case Study
DOX was encapsulated inside
hollow mesoporous copper sulfide
NPs (HMCuS NPs) covered with a
layer of hyaluronic acid (HA).
The outer HA was later degraded
by hyaluronidase, which is highly
expressed in tumor cells, followed
by controlled release of DOX in the
acidic microenvironment of
tumors.
The NPs then responded to NIR
irradiation, inducing strong
apoptosis within tumors. 46
50. For the redox/pH/photo-responsive release of
DOX, Lu and colleagues established a drug
delivery platform comprising both
organosilica and copper sulfide NPs (DOX-
CuS@PMO) that were crosslinked by thiol
bonds
This complicated tristimuli drug delivery
system relied on multiple aspects of the
tumor microenvironment, namely acidic pH
and elevated GSH.
Hence contributing to maximal tumor
specificity and minimal systemic toxicity.
Case Study
47
54. CONCLUSION
The plethora of available literature on stimuli-responsive delivery
systems demonstrates the growing importance for these systems
However, a majority of these systems have not made it past the pre-
clinical stage and only a handful of examples currently have entered
clinical trials
The need for a precise control over the “response” to the applied
“stimulus” makes their clinical translation challenging
The complex synthetic steps and formulation of multiple components
further compounds the issue 51
55. The majority of stimuli-responsive delivery systems are still in the early
stages of development and the optimization of the synthesis procedures
is needed before they can transition into the clinical world
Externally applied “physical” stimuli are easy to control and
manipulate but internal “biological” triggers are not as easily
controlled
Tumors show considerable variation in their physiological status
between patients, organs, or even the same tumors in different species
External stimuli, on the other hand, need improvement to achieve
better tissue penetration without causing any damage, which would
require the optimization of several contributing parameters
Cont…
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