[DDS Research Aimed at Optimizing Gene and Cell Therapies]

Area of Science:

• Biomedical Engineering
• Gene Therapy
• Immunotherapy

Background:

• Optimizing drug delivery systems (DDS) is crucial for effective gene and cell therapies.
• Adenovirus vectors are promising for gene therapy but require improved targeting and reduced off-target effects.
• Controlling in vivo immune cell dynamics is key to enhancing tumor immunotherapy.

Purpose of the Study:

• To develop and evaluate polyethylene glycol-conjugated adenovirus vectors (PEG-Ad) for enhanced tumor targeting and reduced liver accumulation.
• To investigate the efficacy of a tumor-targeting peptide (CGKRK) conjugated to PEG-Ad for improved delivery to metastatic tumors.
• To optimize tumor immunotherapy by controlling the in vivo dynamics of immune cells using cytokines and chemokines.

Main Methods:

• Conjugation of polyethylene glycol (PEG) to adenovirus vectors (Ad) to create PEG-Ad, with varying PEGylation rates (e.g., 90%).
• Attachment of a tumor-targeting peptide, Cys-Gly-Lys-Arg-Lys (CGKRK), to PEG-Ad to create CGKRK-PEG-Ad.
• Intratumoral administration of modified adenovirus vectors carrying cytokines (e.g., interleukin-12) and chemokines (e.g., CCL27) in tumor models.

Main Results:

• A 90% PEGylation rate of Ad optimally reduced liver accumulation and enhanced tumor targeting via the enhanced permeability and retention effect.
• CGKRK-PEG-Ad demonstrated reduced liver accumulation and superior tumor delivery compared to PEG-Ad, showing potent efficacy against metastatic tumors.
• Combined administration of RGD-Ad-CCL27 and RGD-Ad-IL-12 significantly enhanced antitumor effects and increased the infiltration of CD3+ and perforin+ immune cells into tumors compared to RGD-Ad-IL-12 alone.

Conclusions:

• Optimized PEGylation and peptide conjugation of adenovirus vectors significantly improve tumor targeting and therapeutic efficacy.
• Modulating in vivo immune cell dynamics through combined chemokine and cytokine delivery enhances antitumor immunotherapy.
• These strategies hold promise for advancing DDS in gene therapy and cancer immunotherapy.