The intrinsic pathological microenvironment of tumor tissue enforces barriers to the passive diffusion of nanomedicine, which results in inefficient tumor penetration of drugs and unsatisfactory therapeutic efficacy. Various strategies have been developed to improve the tumor penetration of nanomedicine, but they mostly overcome the barriers separately at different steps in a passive diffusion process. Here, the development of a large polymeric nanocarrier, DA T-PPE D&F (≈180 nm), is reported, which 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 DA T-PPE D&F with a similar diameter exhibits efficient penetration into the deep tumor tissue under magnetic actuation and an enhanced reactivation rate of the pH esensitive TAT. Therefore, DA T-PPE D&F is able to efficiently deliver doxorubicin into most tumor cells in vivo, and the superior anticancer effect indicates the potential of DA T-PPE D&F as a universal, responsive, and active nanocarrier to deliver various hydrophobic drugs into the deep tumor tissue.
Rationale: PEGylation of nanocarriers could extend blood circulation time and enhance tumor accumulation via the enhanced permeability and retention (EPR) effect. Unfortunately, the PEG moiety suppresses tumor cell internalization of nanocarriers, resulting in limited therapeutic efficiency (known as the PEG dilemma). Designing stimuli-responsive shell-detachable nanocarriers, which could detach the PEG corona from the nanocarriers in desired tumor tissues in response to the local environment, is an appealing approach to overcome the PEG dilemma, but nanocarrier applications are also limited by a lack of universal stimuli for PEG detachment.Methods: In this study, we synthesized red light-responsive, amphiphilic mPEG bridged to the photosensitizer Ce6 via a thioketal (TK) bond (mPEG-TK-Ce6), which was then used to achieve the PEGylation of polylactide (PLA)-based nanoparticles encapsulating the Pt(IV) prodrug. The therapeutic efficacy of the prepared nanoparticles was evaluated in vitro and in vivo.Results: We demonstrated that the amphiphilic mPEG-TK-Ce6 can realize the PEGylation of Pt(IV) prodrug-loaded PLA nanoparticles and consequently enhanced nanoparticle accumulation in tumor tissues. When the tumor tissues were subjected to 660 nm irradiation, reactive oxygen species (ROS) generated by Ce6 induced the rapid degradation of the adjacent TK bond, resulting in PEG detachment and enhanced tumor cell internalization. Therefore, mPEG-TK-Ce6 facilely achieved PEGylation and light-responsive dePEGylation of the nanocarrier for enhanced antitumor efficacy in nanomedicine.Conclusion: Such red light-responsive amphiphilic mPEG-TK-Ce6 facilely achieved PEGylation and dePEGylation of the nanocarrier, providing a facile strategy to overcome PEG dilemma.
In situ cancer vaccines consisting of antigens and adjuvants
are
a promising cancer treatment modality; however, the convenient manufacture
of vaccines in vivo and their efficient delivery to lymph nodes (LNs)
remains a major challenge. Herein, we outline a facile approach to
simultaneously achieve the in situ programming of vaccines via two
synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of
antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of
generated antigens for the manufacture of nanovaccines in situ and
LN-targeted delivery, which significantly promoted the uptake and
maturation of dendritic cells to initiate potent anticancer immune
responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4),
this therapy completely eradicated distant tumors in some mice and
exerted a long-term immune memory effect on tumor metastasis. This
study provides a generalizable strategy for in situ cancer vaccination.
The passive diffusion performance of nanocarriers results in inefficient drug transport across multiple biological barriers and consequently cancer therapy failure. Here, a magnetically driven amoeba-like nanorobot (amNR) is presented for whole-process active drug transport. The amNR is actively extravasated from blood vessels and penetrated into deep tumor tissue through a magnetically driven deformation effect. Moreover, the acidic microenvironment of deep tumor tissue uncovers the masked targeting ligand of amNR to achieve active tumor cell uptake. Furthermore, the amNR rapidly releases the encapsulated doxorubicin (DOX) after alternating magnetic field application. The amNRs eventually deliver DOX into ≈92.3% of tumor cells and completely delay tumor growth with an inhibition rate of 96.1%. The deformable amNRs, with the assistance of magnetic field application, provide a facile strategy for whole-process active drug transport.
The overexpressed glutathione peroxidase4 (GPX4) and insufficient H 2 O 2 in tumor cells weaken ferroptosis therapy and the elicited anticancer immune response. Herein, a rigid metal-polyphenol shell decorated nanodevice ssPPE Lap @Fe-TA is constructed to successfully overcome the drawbacks of ferroptosis therapy. The ssPPE Lap @Fe-TA consists of a rigid Fe-TA networkbased shell and disulfide-containing polyphosphoester (ssPPE) core with β-lapachone loading. The rigid Fe-TA network-based shell of ssPPE Lap @ Fe-TA enables its efficient internalization by tumor cell and then disintegrates in the acidic endosome/lysosome to initiate Fe 3+ /Fe 2+ conversion-driven ferroptosis. The ssPPE core will deplete glutathione (GSH) via the disulfidethiol exchange reaction to inactivate GPX4, and also trigger the release of β-lapachone to significantly increase intracellular H 2 O 2 and then promote Fe 3+ -mediated Fenton reaction, eventually achieving strong inhibition of tumor progression. Moreover, ssPPE Lap @Fe-TA elicites a robust systemic antitumor immune response by promoting dendritic cells (DCs) maturation and T cell infiltration, and synergizes with anti-PD-L1 antibody (a-PD-L1) to strikingly suppress 4T1 tumor growth and lung metastasis.
Nanomedicines for combining chemotherapy and sonodynamic
therapy
(SDT) have enormous potential in squamous cell carcinoma treatment.
However, the therapeutic efficacy of noninvasive SDT is severely limited
because the generation of reactive oxygen species (ROS) by sonosensitizers
is highly dependent on the levels of intracellular excess glutathione
(GSH) in the tumor cells. To overcome this barrier, a red blood cell
(RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitive
polyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE)
was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin
(HMME) and chemotherapeutic agent docetaxel (DTXL) for effectively
enhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generation
under ultrasound (US) inhibited SCC7 cell proliferation and accelerated
DTXL release to further kill tumor cells via the
hydrophobic–hydrophilic transition of the nanoparticle core.
Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH to
prevent ROS consumption. This biomimetic nanomedicine provides GSH
depletion and amplified ROS generation capabilities to achieve a novel
synergistic chemo-SDT strategy for squamous cell carcinomas.
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