Ultrasound-Activated Cascade Effect for Synergistic Orthotopic Pancreatic Cancer Therapy

Abstract

In some malignant tumor, especially for pancreatic tumor, poor solid-tumor penetration of nanotherapeutics impedes their treatment efficacy. Herein, we develop a polymer-peptide conjugate with the deep tissue penetration ability, which undergoes a cascade process under ultrasound (US), including (1) the singlet oxygen 1 O 2 is generated by P18, (2) the thioketal bond is cleaved by the 1 O 2 , (3) the departure of PEG chains leads to the in situ self-assembly, and (4) the resultant self-assembled PK nanoparticles show considerable cellular internalization. Owing to the synergistic effect of US on increasing the membrane permeability, the endocytosis and lysosome escape of PK nanoparticles are further enhanced effectively, resulting in the improved therapeutic efficacy. Thanks to the high tissue-penetrating depth and spatial precision of US, PTPK presents enhanced tumor inhibition in an orthotopic pancreatic tumor model. Therefore, the US-activated cascade effect offers a novel perspective for precision medicine and disease theranostics.

Trends in Micro‐/Nanorobotics: Materials Development, Actuation, Localization, and System Integration for Biomedical Applications

“…During the past decades, micro‐ and nanoparticle‐based drug delivery systems have been extensively explored. [ 346–354 ] Micro‐ and nanoparticles shows a lot of merits in drug delivery such as controlled release rate, high loading capacity, and rapid kidney removal. [ 355–361 ] However, nanoparticle‐based drug delivery commonly relies on the circulatory system, and lack proper drug‐targeting and barrier‐penetration ability for highly localized therapeutic drug delivery.…”

Precise Control of Self‐assembly in vivo Based on Polymer‐Peptide Conjugates†

“…(C) Schematic illustration of ultrasound (US)‐activated cascade effect of PPCs for orthotopic pancreatic cancer therapy. [ 77 ] Reproduced with permission from Ref. [77].…”

“…[ 73‐74 ] The light and ultrasound (US) were main trigger condition, whereas US has been widely applied in diagnosis, imaging, and disease treatment owing to the nonradiative property and lower tissue attenuation coefficient than light. [ 75‐76 ] Our group [ 77 ] reported the US‐activated process of PPCs self‐assembly for deep penetration and effective endocytosis in pancreatic tumor. The hydrophilic mPEG with singlet oxygen 1 O 2 ‐cleavable thioketal bond and sonosensitizer (purpurin 18, P18) were decorated onto cytotoxic peptide KLAK to synthesize PEG‐tk‐(P18) KLAK (PTPK).…”

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance

“…Despite this advantage, potential hurdles exist in that it is now standard practice to formulate therapeutic nanoparticles with a ‘stealth’ PEG corona to evade macrophage recognition and clearance from the circulation. Engineering of nanoparticles with environmentally-responsive properties could provide an innovative solution to this challenge, whereby protective coatings such as PEG are designed to remain intact in the bloodstream followed by detachment upon reaching the tumour site [ 176 , 177 , 178 , 179 ]. As demonstrated by Han et al, this can be achieved by grafting PEG chains onto nanoparticles via matrix metalloproteinase-9 (MMP-9)-labile linkers, which are cleaved upon encountering high levels of the protease in the pancreatic tumour microenvironment [ 180 ].…”