Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimer's disease

Qian Guo; Yixian Li; Shuting Xu; Pengzhen Wang; Kang Qian; Peng Yang; Dongyu Sheng; Liuchang Wang; Yunlong Cheng; Ran Meng; Jinxu Cao; Haichang Luo; Yan Wei; Qizhi Zhang

doi:10.1016/j.jconrel.2023.01.074

Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimer's disease

J Control Release. 2023 Mar:355:604-621. doi: 10.1016/j.jconrel.2023.01.074. Epub 2023 Feb 16.

Authors

Qian Guo¹, Yixian Li², Shuting Xu², Pengzhen Wang², Kang Qian², Peng Yang², Dongyu Sheng², Liuchang Wang², Yunlong Cheng², Ran Meng², Jinxu Cao², Haichang Luo², Yan Wei³, Qizhi Zhang⁴

Affiliations

¹ Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China; Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
² Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
³ Institute of Translational Medicine, Shanghai University, Shanghai 200436, China. Electronic address: ywei@shu.edu.cn.
⁴ Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China. Electronic address: qzzhang@fudan.edu.cn.

PMID: 36738970
DOI: 10.1016/j.jconrel.2023.01.074

Abstract

Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a β-sheet breaker acting on Aβ, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aβ, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aβ and p-tau, confirming the promising application of nano-combination strategy in AD treatment.

Keywords: Alzheimer's disease; Anti-Aβ; Anti-tau; Brain-neuron targeting; Nano-combination therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / therapy
Amyloid beta-Peptides / metabolism
Animals
Brain / metabolism
Disease Models, Animal
Mice
Mice, Transgenic
Nanoparticles*
Neurons / metabolism
Peptides / pharmacology
Peptides / therapeutic use

Substances

Peptides
monomethoxypolyethyleneglycol-polylactide block copolymer
Amyloid beta-Peptides