TY - JOUR
T1 - Poly(alkylideneamine) Dendrimer Nanogels Codeliver Drug and Nucleotide To Alleviate Anticancer Drug Resistance through Immunomodulation
AU - Gao, Yue
AU - Ouyang, Zhijun
AU - Li, Gaoming
AU - Yu, Qiuyu
AU - Dai, Waicong
AU - Rodrigues, João
AU - Pich, Andrij
AU - Abdul Hameed, Meera Moydeen
AU - Shen, Mingwu
AU - Shi, Xiangyang
N1 - Funding Information:
This research was financially supported by the National Key R&D Program (No. 2022YFE0196900), the National Natural Science Foundation of China (Nos. 52350710203 and U23A2096), the Science and Technology Commission of Shanghai Municipality (Nos. 23520712500, 21490711500, 23WZ2503300 and 20DZ2254900), the Fundamental Research Funds for the Central Universities (Nos. CUSF-DH-D-2022059 and 2232021A-03), and China Scholarship Council. X.S. and J.R. thank the support from FCT-Fundação para a Ciência e a Tecnologia through the CQM Base Fund - UIDB/00674/2020 (DOI: 10.54499/UIDB/00674/2020). This project was also supported by the Researchers Supporting Project (No. RSPD2024R769), King Saud University, Riyadh, Saudi Arabia.
Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/2/5
Y1 - 2024/2/5
N2 - The development of drug delivery strategies with the desired immunomodulation effects to alleviate tumor drug resistance remains a challenge. Herein, low-generation poly(alkylideneamine) dendrimer nanogels (DNGs) were developed to codeliver chemotherapeutics 5-fluorouracil (5-FU) and immune agonist cyclic GMP-AMP (cGAMP) for tumor chemoimmunotherapy. The DNGs possess a hydrodynamic size of 145.6 nm, excellent drug/nucleotide coloading capacity, and pH-sensitive drug release profile. The 5-FU-loaded DNGs can overcome 5-FU resistance through prolonged cellular retention and downregulation of P-glycoprotein expression on the cancer cell surface. Meanwhile, the cGAMP in the codelivery system can activate the stimulator of interferon genes pathway in cancer cells, which further relives drug resistance and modulates tumor microenvironment through maturation of dendritic cells and macrophage M1 polarization. The immunomodulation-facilitated drug resistance alleviation was confirmed in vivo in a subcutaneous colorectal tumor mouse model, leading to relatively long tumor drug retention, inhibition of tumor growth, and generation of active antitumor immune responses.
AB - The development of drug delivery strategies with the desired immunomodulation effects to alleviate tumor drug resistance remains a challenge. Herein, low-generation poly(alkylideneamine) dendrimer nanogels (DNGs) were developed to codeliver chemotherapeutics 5-fluorouracil (5-FU) and immune agonist cyclic GMP-AMP (cGAMP) for tumor chemoimmunotherapy. The DNGs possess a hydrodynamic size of 145.6 nm, excellent drug/nucleotide coloading capacity, and pH-sensitive drug release profile. The 5-FU-loaded DNGs can overcome 5-FU resistance through prolonged cellular retention and downregulation of P-glycoprotein expression on the cancer cell surface. Meanwhile, the cGAMP in the codelivery system can activate the stimulator of interferon genes pathway in cancer cells, which further relives drug resistance and modulates tumor microenvironment through maturation of dendritic cells and macrophage M1 polarization. The immunomodulation-facilitated drug resistance alleviation was confirmed in vivo in a subcutaneous colorectal tumor mouse model, leading to relatively long tumor drug retention, inhibition of tumor growth, and generation of active antitumor immune responses.
U2 - 10.1021/acsmaterialslett.3c01426
DO - 10.1021/acsmaterialslett.3c01426
M3 - Article
SN - 2639-4979
VL - 6
SP - 517
EP - 527
JO - ACS Materials Letters
JF - ACS Materials Letters
IS - 2
ER -