Switchable PAMAM megamers for deep tumor penetration and enhanced cell uptake

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Drug Delivery

Background:

• Current nanoparticle drug delivery systems face challenges in tumor penetration and cell uptake.
• Optimizing nanocarrier properties is crucial for effective anticancer drug delivery.

Purpose of the Study:

• To develop size and charge switchable polyamidoamine (PAMAM) megamers (SChPMs) for enhanced doxorubicin (DOX) delivery.
• To evaluate the efficacy and safety of SChPMs in overcoming physiological barriers and drug resistance.

Main Methods:

• Fabrication of SChPMs using PAMAM dendrimers with pH-sensitive bonds and PEGylation.
• Characterization of SChPM size and charge at different pH values (7.4 and 6.5).
• In vitro studies on multicellular spheroids and cell internalization; in vivo studies in 4T1 tumor-bearing mice.

Main Results:

• SChPMs exhibited a significant size reduction (100 nm to 15 nm) and charge increase (+0.75 mV to +6.7 mV) at tumor-relevant acidic pH (6.5).
• Enhanced penetration into multicellular spheroids and improved cell internalization were observed.
• DOX-loaded SChPMs (DSChPMs) demonstrated potent antitumoral activity with minimal toxicity to vital tissues in mice.

Conclusions:

• The developed SChPMs offer a versatile and agile platform for targeted drug delivery.
• These nanocarriers effectively overcome tumor penetration barriers and physiological resistance to anthracycline drugs.
• The promising results warrant further investigation for potential clinical applications in cancer therapy.