Up to now, dozens of anticancer nanomedicines have been approved for clinical applications. However, clinical evidences demonstrated that these nanomedicines efficiently reduced toxicity but failed to improve therapeutics efficacy compared to conventional formulations. One key reason is the elevated interstitial fluid pressure, high extracellular matrix density, and disorganized vascular networks severely prevent the passive diffusion of nanoparticles into the deep tumor tissue which result in insufficient penetration into tumor parenchyma. The strategies that have been developed to improve tumor penetration of nanoparticles based on passive diffusion process are inefficient. Therefore, it is urgent to develop a system that can overcome multiple biological barriers in tumor tissue and achieve active deep tumor penetration. We report the development of a deformable polymeric nanocarrier (DAT-PPED&F), with a diameter of 180 nm under magnetic actuation, for deep tissue penetration. It comprises a flowable polyphosphoester core, ferrimagnetic nanocubes, and a tumor extracellular pH-sensitive transactivator of transcription (TAT). Compared with a polylactic acid-based nanocarrier with a rigid core, this deformable DAT-PPED&F with a similar diameter exhibits efficient penetration into the deep tumor tissue under magnetic actuation and an enhanced reactivation rate of the pHe-sensitive TAT. Moreover, our results confirm that DAT-PPED&F under magnetic actuation actively penetrated into tumor tissue due to its deformation capability. Overall, the deformable DAT-PPED&F achieve active deep tumor penetration and efficiently deliver doxorubicin into most tumor cells in vivo under magnetic actuation, enabling superior tumor growth inhibition after treatments. The deformable DAT-PPED&F, with the assistance of magnetic field application, provides a facile strategy for achieve active deep tumor penetration.

Magnetically actuated active deep tumor penetration of deformable nanocarriers for enhanced cancer therapy

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