Selective targeting and therapy of metastatic and multidrug resistant tumors using a long circulating podophyllotoxin...

Area of Science:

• Oncology
• Nanotechnology
• Pharmacology

Background:

• Metastatic and multidrug-resistant (MDR) cancers have limited treatment options.
• Podophyllotoxin (PPT), an anti-tubulin agent, shows high potency against MDR tumors but has poor solubility and non-specificity.
• Systemic administration of PPT is challenging due to its physicochemical properties.

Purpose of the Study:

• To develop a novel nanoparticle dosage form of PPT (Celludo) for improved efficacy against metastatic and MDR tumors.
• To evaluate the pharmacokinetic profile and anti-tumor efficacy of Celludo in preclinical models.

Main Methods:

• Celludo was developed by covalently conjugating PPT and polyethylene glycol (PEG) to acetylated carboxymethyl cellulose (CMC-Ac) via ester linkages.
• Pharmacokinetic parameters (half-life, AUC, clearance) were compared between Celludo and free PPT.
• Anti-tumor efficacy and survival were assessed in lung and ovarian metastatic cancer models.

Main Results:

• Celludo demonstrated an 18-fold prolonged half-life, 9000-fold higher AUC, and 1000-fold reduced clearance compared to free PPT.
• Tumor delivery was 500-fold higher with Celludo.
• Celludo significantly increased median survival in lung and ovarian metastatic models, outperforming docetaxel and standard therapy.

Conclusions:

• Celludo is an effective nanoparticle formulation for delivering PPT, showing enhanced pharmacokinetic properties and superior anti-tumor activity.
• Celludo demonstrates significant potential as a therapeutic agent for metastatic and MDR tumors with no major detected toxicity.