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Enzymes in Drug Delivery Systems

Introduction to ERDDS

Enzyme Responsive drug delivery systems (ERDDS) are designed to release

antibiotics in response to specific enzymatic triggers that are often found at disease sites.

This system is effective in offering precise control over a drug release, as they release only

when the disease site is found/targeted. (ERDDS)’s also help to minimize off-target

effects. This allows for doctors to use more powerful drugs and more of them, and not be

concerned about the well being of a patient.

Overview of Operation of ERDDS

ERDDS exploit the presence of disease-specific enzymes or overexpressed enzymes

that are associated with conditions. For example, those with Leukemia have an

overexpression of the enzyme FLT3 (Fms-like tyrosine kinase 3), which plays a role in cell

growth. ERDDS catalyze specific reactions that trigger the release of drugs from the

delivery system, but only when an overexpression is targeted. ERDDS act as an

encapsulator that stores the drug until it is useful.

Types of ERDDS

There are several types of ERDDS for several different types of situations, but they

all function with the same intent, the storing and releasing of drugs at the correct

moment.

➢ Enzyme-Cleavable Prodrugs
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○ Enzyme-Cleavable Prodrugs are inactive forms of drugs that undergo a

process called “Enzymatic Cleavage” at the target site. Enzymatic cleavage is

where enzymes break down larger molecules into smaller pieces by cutting

specific chemical bonds. Enzyme-responsive prodrugs are designed with

cleavable bonds susceptible to hydrolysis, during which one part of the

water molecule attaches to a fragment of the prodrug, while the other part

of water attaches to the other fragment. This causes the bond to break,

leading to the release of the active drug. This approach enables site-specific

activation, because if the drug never encounters a specific environment, the

drug will not be released.

○ An example of these prodrugs is Irinotecan, which is used in the treatment

of various cancers. In its active form, this drug can cause severe side effects,

to mitigate this Irinotecan is administered as the prodrug called CPT-11.

This enzyme helps the selectivity of Irinotecan, enabling targeted delivery

of the drug to tumor tissues, minimizing adverse effects.

➢ Enzyme-Responsive Nanoparticles

○ Enzyme-Responsive Nanoparticles can be engineered to respond to

enzymatic stimuli. These nanoparticles are loaded with drug molecules and

coated with enzyme cleavable molecules. Upon encountering the target

enzyme, the nanoparticles undergo degradation, releasing the encapsulated

drugs.
 ○ Paclitaxel is a potent chemotherapeutic agent used in the treatment of

various cancers, including breast, ovarian, and lung cancers. Releasing them

with nanoparticles helps to prevent premature release of the drug during

circulation. This aids in the drug's effectiveness, because the drug is

released directly at the tumor site.

➢ Enzyme Responsive Hydrogels

○ Hydrogels are networks of crosslinked polymers that are capable of

absorbing and retaining large amounts of water. Enzyme- responsive

hydrogels can be designed to incorporate enzyme-cleavable peptides or

polymers within their structure. Upon exposure to the target enzyme, the

hydrogel undergoes degradation and releases the entrapped drug just like

enzyme responsive nanoparticles.

○ A specific example of a hydrogel is a system designed for the controlled

release of insulin in response to glucose levels, mimicking the function of

pancreatic cells. As glucose levels decrease, the enzymatic activity

diminishes, resulting in the stabilization of the hydrogel and the stopping of

insulin release. By releasing insulin in a glucose responsive manner, this

enzymatic hydrogel can potentially improve glycemic control and reduce

the risk of hypoglycemia.

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Advantages of ERDDS

➢ Targeted Delivery

○ As stated, ERDDS enable precise targeting of drug agents to specific disease

sites, reducing unwanted exposure to off target areas of the body.

➢ Enhanced Resistance

○ By releasing drugs in response to enzymatic triggers, ERDDS can minimize

drug resistance, and therefore more treatments can be administered in a

shorter period of time.

➢ Reduced Toxicity

○ Controlled and localized drug release minimizes exposure to healthy tissue,

reducing the risk of side effects.

➢ Flexibility

○ As spoken about in “Types of ERDDS” certain diseases require certain

pathways of treatments, ERDDS can be tailored to respond to disease-

specific enzymes, allowing for versatile applications.

Applications of ERDDS

➢ Cancer Therapy

○ ERDDS have shown promise in cancer therapy by selectively delivering

chemotherapeutic agents to tumor tissues while keeping healthy cells

intact.

➢ Inflammatory Diseases
 ○ ERDDS can be employed to deliver anti-inflammatory agents to sites of

inflammation, where certain enzymes are overexpressed.

➢ Wound Healing

○ Enzyme-responsive dressings have been developed for wound healing

applications, by way of antimicrobial agents in response to enzymes present

in the wound’s environment.

Summary

Enzyme-responsive drug delivery systems (ERDDS) offer precise control of the

release of drugs at disease sites by exploiting disease-specific or overexpressed enzymes.

ERDDS employ strategies such as cleavable prodrugs, enzyme-responsive nanoparticles,

and enzyme-responsive hydrogels.

ERDDS provide targeted drug delivery, localizing drug delivery to disease sites

while minimizing off-target effects, by releasing drugs in response to disease specific

enzymatic triggers, ERDDS enhance drug efficiency, reduce drug resistance, and lower

toxicity.These systems are being applied to treat various problems, including cancer

therapy, inflammatory diseases, and wound healing.

To conclude, enzyme-responsive drug delivery systems represent a promising step

in drug delivery research. With their ability to achieve targeted delivery, enhance

efficiency, and minimize risks, ERDDS hold immense potential for revolutionizing the

treatment of many diseases.

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Works Cited

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delivery systems in cancer treatment. Journal of controlled release : official journal of the Controlled Release

Society. https://pubmed.ncbi.nlm.nih.gov/31295542/

Sobczak, M. (2022, April 16). Enzyme-responsive hydrogels as potential drug delivery systems-state of

knowledge and future prospects. MDPI. https://www.mdpi.com/1422-0067/23/8/4421

Li, M., Zhao, G., Su, W.-K., & Shuai, Q. (2020, June 22). Enzyme-responsive nanoparticles for anti-tumor

drug delivery. Frontiers. https://www.frontiersin.org/articles/10.3389/fchem.2020.00647/full

PMC, E. (n.d.). Europe PMC. https://europepmc.org/article/med/31295542

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