Ultrasound-Responsive Peptide Nanogels to Balance Conflicting Requirements for Deep Tumor Penetration and Prolonged Blood Circulation

Min Sun, Tao Yue, Congyu Wang, Zhen Fan*, Ehud Gazit*, Jianzhong Du*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

A series of biological barriers need to be overcome for therapeutic nanocarriers accumulating at the tumor site and uptaken by cancer cells. One strategy is to construct switchable nanocarriers to meet the conflicting requirements for various physiology environments. In this work, besides widely studied endogenous stimuli-responsiveness, an exogenous ultrasound responsiveness was additionally embedded into nanocarriers to balance the conflicting needs of prolonged blood circulation and deep tumor penetration. Polylysine and Pluronic F127 were first coassembled and then cross-linked by genipin to form stable nanogel structure. Subsequently, ICAM-1 antibody was grafted onto the nanogel (designated as GenPLPFT) for active tumor targeting. Upon external sonication, the F127 was shed from GenPLPFTto induce swelling of nanogel with reduced stability and accelerated drug release. In detail, sonication leads to GenPLPF swelling from 329 to 516 nm, while its Young's modulus significantly decreased from 336.78 to 3.93 kPa. Through intravenous injection, relatively rigid GenPLPFTwas able to achieve a high level of accumulation at tumor site by active targeting and long-term blood circulation. Moreover, under sonication at the tumor site, GenPLPFTbecame softer with enhanced deformability to achieve deep tumor penetration. In addition, in vivo studies revealed that GenPLPFTwas able to penetrate into the deep area of xenografted tumor with enhanced antitumor efficacy and reduced toxicity. Overall, this peptide nanogel with ultrasound-responsive stiffness demonstrates an effective approach to overcome a series of biological barriers for enhanced deep tumor therapy.

Original languageEnglish
Pages (from-to)9183-9194
Number of pages12
JournalACS Nano
Volume16
Issue number6
DOIs
StatePublished - 28 Jun 2022

Funding

FundersFunder number
Shanghai international scientific collaboration fund21520710100
Natural Science Foundation of Shanghai19ZR1478800
National Natural Science Foundation of China61803250, 21925505, 22075212
Science and Technology Commission of Shanghai Municipality19QA1403700
National Key Research and Development Program of China2018YFB1304503

    Keywords

    • cancer therapy
    • deep penetration
    • drug resistance
    • nanogel
    • peptide
    • ultrasound-responsive

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