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Synthesis of Aptamer-PEI-g-PEG Modified Gold Nanoparticles Loaded with Doxorubicin for Targeted Drug Delivery
Published on: June 23, 2020
Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems
Oktay Tacar1, Pornsak Sriamornsak, Crispin R Dass
1School of Biomedical and Health Sciences, Victoria University, St Albans, Australia.
Objectives:
The frontline drug doxorubicin has been used for treating cancer for over 30 years. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life-threatening cardiotoxicity, which forces the treatment to become dose-limiting.
Key Findings:
Doxorubicin is known to bind to DNA-associated enzymes, intercalate with DNA base pairs, and target multiple molecular targets to produce a range of cytotoxic effects. For instance, it causes the activation of various molecular signals from AMPK (AMP-activated protein kinase inducing apoptosis) to influence the Bcl-2/Bax apoptosis pathway. By altering the Bcl-2/Bax ratio, downstream activation of different caspases can occur resulting in apoptosis. Doxorubicin also induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse affects including liposomes, hydrogel and nanoparticulate systems, and we highlight the pros and cons of these drug delivery systems.
Summary:
Overall the future for the continued use of doxorubicin clinically against cancer looks set to be prolonged, provided certain enhancements as listed above are made to its chemistry, delivery and toxicity. Increased efficacy depends on these three aims being met satisfactorily as discussed in turn in this review.
Insights
Doxorubicin is a vital cancer drug, but its toxicity limits treatment. Enhancing its delivery and chemistry can improve efficacy and reduce side effects for better cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Doxorubicin, a frontline chemotherapy agent for over 30 years, offers cures in some cases but causes dose-limiting organ toxicities, particularly cardiotoxicity.
- Its mechanism involves DNA intercalation and targeting of enzymes, leading to apoptosis via pathways like AMPK and Bcl-2/Bax.
- Adverse effects extend to healthy tissues including brain, liver, kidney, and heart.
Purpose of the Study:
- To review the mechanisms of doxorubicin-induced toxicity.
- To evaluate various drug delivery systems designed to mitigate doxorubicin's adverse effects.
- To discuss future directions for enhancing doxorubicin's clinical utility.
Main Methods:
- Literature review of doxorubicin's molecular targets and cytotoxic effects.
- Analysis of different drug delivery systems (liposomes, hydrogels, nanoparticles).
- Evaluation of pros and cons of existing and emerging delivery strategies.
Main Results:
- Doxorubicin induces apoptosis and necrosis through multiple molecular pathways, including AMPK activation and Bcl-2/Bax ratio alteration.
- Drug delivery systems like liposomes and nanoparticles show promise in reducing systemic toxicity.
- Each delivery system presents unique advantages and disadvantages regarding efficacy and safety.
Conclusions:
- Continued clinical use of doxorubicin is likely, contingent upon chemical modifications and improved delivery systems.
- Enhancing doxorubicin's chemistry, delivery, and reducing toxicity are crucial for increasing its overall efficacy.
- Future research should focus on optimizing these aspects to prolong doxorubicin's therapeutic lifespan.
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