A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• The nucleus is a key target for antitumor agents in cancer therapy.
• Effective drug delivery to the tumor cell nucleus remains a challenge.

Purpose of the Study:

• To develop a smart polymeric conjugate platform for multistage nuclear drug delivery.
• To achieve targeted delivery of antitumor agents to the cancer cell nucleus upon systemic administration.

Main Methods:

• A smart polymeric conjugate platform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer was designed.
• Detachable, enzyme-sensitive nucleus transport subunits with a biforked structure were incorporated.
• These subunits featured a model drug (H1 peptide) and a novel pH-responsive targeting peptide (R8NLS) combining cell penetrating peptide and nuclear localization sequence functionalities.

Main Results:

• The conjugates demonstrated prolonged circulation time and enhanced tumor homing.
• Activation of R8NLS in the acidic tumor microenvironment improved tissue penetration and cellular uptake.
• A 50-fold increase in nuclear drug accumulation was observed in vitro, with excellent in vivo nuclear drug delivery efficiency.

Conclusions:

• The developed platform enables efficient systemic nuclear drug delivery.
• Combining microenvironment-responsive structures and detachable subunits is a viable strategy for targeted nuclear drug delivery in cancer therapy.