Human ribonuclease with a pendant poly(ethylene glycol) inhibits tumor growth in mice

Area of Science:

• Biochemistry
• Enzymology
• Cancer Biology

Background:

• Human pancreatic ribonuclease 1 (RNase 1) is a cationic enzyme that cleaves RNA and can enter cells.
• RNase 1 is rapidly cleared from circulation, limiting its therapeutic potential.
• Tumor growth inhibition requires sustained intracellular enzyme activity.

Purpose of the Study:

• To enhance the in vivo efficacy of RNase 1 by improving its pharmacokinetic properties.
• To evaluate the anti-tumor activity of RNase 1 conjugated with polyethylene glycol (PEG).
• To determine the correlation between PEG size, circulation persistence, and anti-tumor efficacy.

Main Methods:

• Conjugation of RNase 1 with varying sizes of poly(ethylene glycol) (PEG) moieties.
• Assessment of ribonucleolytic activity of RNase 1-PEG conjugates.
• Evaluation of pharmacokinetic properties, including circulation half-life.
• Testing anti-tumor efficacy in a xenograft mouse model of human lung cancer.

Main Results:

• PEGylation did not affect the ribonucleolytic activity of RNase 1.
• RNase 1-PEG conjugates exhibited increased persistence in circulation, dependent on PEG size.
• A 60-kDa PEG conjugate demonstrated significant inhibition of tumor growth in vivo.
• The efficacy of the RNase 1-PEG conjugate was approximately 5000-fold greater than erlotinib.

Conclusions:

• Polyethylene glycol (PEG) conjugation enhances the in vivo efficacy of human RNase 1.
• PEGylated RNase 1 demonstrates potent anti-cancer activity with potential clinical utility.
• This approach converts an endogenous enzyme into a promising cytotoxin for cancer therapy.