Biodynamers as prodrugs with controlled uptake and activity

Area of Science:

• Polymer Chemistry
• Drug Delivery Systems
• Cancer Therapeutics

Background:

• Chemotherapy faces limitations due to toxicity to healthy tissues, hindering drug approval.
• Adenosine dialdehyde (ADOX), a potent anti-cancer agent, exhibits significant side effects.
• Targeting cancer cells in the acidic tumor microenvironment (TME) remains a challenge.

Purpose of the Study:

• To develop a polymeric prodrug of ADOX to reduce systemic toxicity and enhance tumor selectivity.
• To create pH-responsive ADOX-biodynamers that release ADOX in the acidic TME.
• To evaluate the safety, efficacy, and cellular uptake of ADOX-biodynamers.

Main Methods:

• Synthesized ADOX-biodynamers using dynamic constitutional chemistry with pH-responsive dynamic covalent bonds.
• Investigated ADOX release kinetics at different pH conditions (acidic vs. neutral).
• Assessed cytotoxicity in non-cancerous and cancerous cell lines, cellular uptake, and spheroid penetration.

Main Results:

• ADOX-biodynamers showed significantly faster ADOX release in acidic conditions (pH 5.5) compared to neutral conditions (pH 7.4).
• The ADOX-biodynamer (ALB) demonstrated reduced toxicity in non-cancerous cells at neutral pH and restored cytotoxicity in cancer cells under acidic conditions.
• ALB exhibited enhanced cellular uptake in acidic conditions and effectively reduced tumor spheroid size in vitro.

Conclusions:

• ADOX-biodynamers offer improved safety profiles by minimizing toxicity to healthy cells at physiological pH.
• The pH-responsive drug release mechanism enhances ADOX's efficacy and selectivity towards cancer cells in the TME.
• Polymeric prodrugs utilizing dynamic covalent bonds represent a promising strategy for developing safer and more effective cancer therapeutics.