This document discusses enzyme-activated drug delivery systems. It describes how enzymes can directly release drugs from carriers upon site-specific cleavage or facilitate drug release by generating products that alter carrier properties. Typical enzymes discussed include matrix metalloproteinases, phospholipases, and oxidoreductases. Popular carrier approaches activated by enzymes are polymeric nanoparticles, liposomes, and hybrid inorganic/organic nanoparticles. The document provides examples of how each carrier type can be designed to respond to specific enzymes and selectively release drugs.

1. ENZYME-
ACTIVATED
DRUG
DELIVERY
SYSTEMS
M E H A K A G G A R WA L
M . P H A R M ( P H A R M A C E U T I C S )
H I M A C H A L I N S T I T U T E O F P H A R M A C Y

2. CONTENT
Introduction
Typical enzymes for controlled drug delivery
Polymeric nanoparticle
Liposome
Hybrid nanoparticle
Inorganic nanoparticle
References

3. INTRODUCTION
oEnzymes act as triggers in drug delivery systems because they are substrate specific and have high
selectivity.
oSince enzymes (such as glycosidases, lipase, phospholipases or proteases) are related to almost all
the biological and metabolic process, they can be use to get enzyme-mediated drug release.
oDrug carriers can be activated by enzymes to expose the targeting ligand for the subsequent
internalization into specific cells. Enzymes can facilitate the generation of specific products promoting
drug release from carriers.

4. (A) Drugs can be directly released from a variety of carriers upon site-specific cleavage by enzymes.
(B) Drug carriers can be activated by enzymes to expose targeting ligands for the subsequent cellular
delivery.
(C) Enzymes can facilitate the generation of specific products that result in drug release from carriers.

5. oPopular strategies involve polymeric assemblies and liposomes that disintegrate, undergo structural
reorganization, or cleavage to release functionalized ligands. Enzymes directly govern these changes
or enzymatic products trigger advantageous changes in the physiochemical properties of the
nanomaterial.

6. TYPICAL ENZYMES FOR
CONTROLLED DRUG DELIVERY
Matrix metalloproteases (MMP) are known to be involved in many physiological processes such as
tissue remodeling, wound healing and tumor invasion.
oMMP subtypes are divided into two classes-
Transmembrane enzymes and Extra-cellular enzymes
oMMPs play a vital role in invasion, angiogenesis, and metastasis to cancer.
oMMPs are proteolytic enzymes causing degradation of proteins which regulates various cell behavior
for cancer biology.
6 subtypes 18 subtypes

7. Phospholipase up-regulation is pathological indicator for multiple kinds of cancers and many other
disease processes, including inflammation, thrombosis, congestive heart failure.
Secretory phospholipase A2 catalyzes the hydrolysis of phospholipids in the Sn-2 position, generating
free fatty acids and lysophospholipids.
Oxidoreductase is an enzyme which generates diabetes and cancer oxidative environments.
Glucose oxidase (GO) is extensively utilized in controlled release systems or a diagnostic tool in
detention of glucose value.

8. POLYMERIC NANOPARTICLES
oBiodegradable polymeric nanoparticles are promising approach to delivery drugs within an optimal
dosage range.
oBiodegradable polymeric nanoparticles are beneficial in increased therapeutic efficacy of the drug,
mitigated side effects, and improved patient compliance.
oEnzyme-responsive polymeric nanoparticles have release drug with taking advantage of dysregulated
enzymes in the disease tissue e.g., overexpressed MMPs in most tumor tissue and reversible or
irreversible changes in chemical structures and / or properties of polymeric materials in response to
specific enzymes.
oWorking of polymeric NPs is shown below:

9. Enzyme degradable NPs are formulates with type A gelatin crosslinked with glutaraldehyde in which PEG-
stabilized quantum dots are distributed.
NPs moves out of blood vessels of tumor by enhanced permeation and retention effect (EPR).
NPs are exposed to upregulated matrix metalloproteinases (MMP-2).
NPs are degraded by MMP.
10nm quantum dot release.
Enhancement of diffusion transport and deep penetration in tumor tissues.

10. oPolymeric NPs shows increase in size by cleave substrates trigger enzymes. A hydrophobic block and
a hydrophilic peptide were integrated into copolymers to prepare micelles. Micelles passively diffused
into tumors and accessed to overexpressed enzymes.

11. LIPOSOME
oLiposomes are used for cancer because of their suitable size, unique chemical properties, large
surface area, structural density and multifunctionality.
oSmart liposome development is done by incorporating enzyme-responsive substrates.
oLiposome can target the tissue of interest either passively or actively via the modification of targeting
molecules that recognize receptors on cell surface.

12. HYBRID NANOPARTICLES
oThe preparation of organic/ inorganic hybrid nanoparticles composed of organic polymers and/ of
inorganic colloids has been recently pursued as a route to combine the advantageous properties of
both classes of macromolecules into one nanoparticle.
oA hybrid design (core and shell structure) could take advantages of both organic/inorganic materials
in the core and shell.
oAmong the various emerging hybrid nanoparticles (e.g. lipid-polymer, gel-lipid, silica (SiO2)-polymer,
iron oxides- polymer hybrid nanoparticle), enzyme-responsive hybrid nanoparticle are gaining
increasing attraction as a new platform for drug delivery because their enzymatic properties can be
engineered according to interest.

13. INORGANIC NANOPARTICLES
oInorganic nanoparticles, especially enzyme-responsive silica nanoparticles (Si-MPs), have great
potential for useful applications in nanomedicine due to their unique responsiveness.
oSi-MPs are equipped with gatekeepers are enormously appealing are being implemented in
controlled release systems.
oEnzyme-responsive Si-MPs were composed of the surface cyclodextrin (CD) gatekeepers; block the
porous channel, which get hydrolyzed in the presence of a-amylase. Afterwards stalk was degraded
by lipase cause release of core. This permitted the Si-MPs to exhibit enzyme-responsive
characteristics.

14. REFERENCES
•Ahad HA., Haranath C., Vikas SS., Varam NJ., Ksheerasagrare T., Gorantla SPR., (2021), A review on
enzyme acting drug delivery system, Research journal of pharmacy and technology, 14(1).
•Hu Q., Katti PS., Gu Z., (2014), Enzyme-responsive nanomaterials for controlled drug delivery,
Nanoscale, 6(21), 12273-12286.
•Lee Y., Thompson DH., (2017), Stimuli-responsive liposomes for drug delivery, Wiley interdiscip rev
nanomed nanobiotechnol., 9(5).
•Fouladi F., Steffen KJ., Mallik S., (2017), Enzyme-responsive liposomes for the delivery of anticancer
drugs, Bioconjug Chem., 28(4), 857-868.
•Goldbart R., Traitel T., Lapidot SA., Kost J., (2002), Enzymatically controlled responsive drug delivery
sytems, Polymers for advanced technologies, 13(10-12), 1006-1018.