Trident Molecule with Nanobrush–Nanoparticle–Nanofiber Transition Property Spatially Suppresses Tumor Metastasis

Abstract

Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap–Phe–Phe–Lys­(SA-CPT)–Lys­(SA-HCQ)–Tyr­(H2PO3)–OH (Nap–CPT–HCQ–Yp) with three functional “spears” (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush–nanoparticle–nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, Nap–CPT–HCQ–Yp undergoes nanobrush–nanoparticle–nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of Nap–CPT–HCQ–Yp enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and Nap–CPT–HCQ–Yp-mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of “smart” multifunctional prodrugs to spatially suppress tumor metastasis.

Interrelation between Programmed Cell Death and Immunogenic Cell Death: Take Antitumor Nanodrug as an Example

“…Chloroquine (CQ) is a common inhibitor of autophagy. [189][190][191] For example, Wu group used amphiphilic block copolymers and hydrophilic HA in situ self-assembly to form nano-micellar dissolvable microneedles (DMNs) patches for delivering autophagy inhibitor CQ and photosensitizer IR780 (Figure 13). DMNs were dissolved after being inserted into the skin.…”

Intracellular Enzyme-Instructed Self-Assembly of Peptides (IEISAP) for Biomedical Applications

“…The IEISAP materials have shown great potential for their application in drug delivery, because they can increase therapeutic efficacy and reduce undesired side effects. Generally, conventional anticancer drugs, such as taxol [ 104 , 105 , 106 , 107 , 108 ], paclitaxel [ 109 ], 10-hydroxyl camptothecin [ 110 ], aldoxorubicin (aldox) [ 78 ], cisplatin or its derivative [ 111 , 112 ], and camptothecin [ 113 ], photosensitizers, such as AIE luminogen (TPE-Py) [ 51 ] and ICG [ 114 ], photothermal agents, such as cypate [ 115 ] and gold nanoparticles [ 116 ], and autophagy inhibitor hydroxychloroquine [ 113 , 115 ], have been loaded to IEISAP materials by chemical conjugation to generate drug-peptide hybrids. Upon encountering various enzymes in vivo, such as ALP [ 105 , 106 , 107 , 110 , 111 , 115 ], furin [ 104 ], MMPs [ 109 , 112 ], and CES [ 115 ], these drug-peptide hybrids can be assembled into different nanostructures, mainly nanofibers [ 78 , 105 , 106 , 107 , 110 , 111 , 112 ], nanoparticles [ 104 , 109 , 115 ], and aggregates [ 51 ].…”

19F Barcoding Enables Multiplex Detection of Biomarkers Associated with Organ Injury and Cancer

“…[3][4][5][6] Cancer is another example that a set of biomarkers need to be analyzed for accurate diagnosis even with biopsy results. [7,8] Furthermore, the deconvolution of complex interacting networks for in-depth understanding of a specific biological process often requires simultaneous detection of various biomarkers. For drug-induced organ injuries, especially those of liver and kidney, which are the two major sites for xenobiotic metabolism, the differentiation between the changes due to the variations of normal metabolism (e.g., drug metabolism) and the changes due to aberrant metabolism caused by injuries, entails the comprehensive analysis of multiple biomarkers.…”

“…For example, the diagnosis of drug‐induced organ injuries, which cause millions of emergency department visits annually, requires simultaneous measurements on the levels of multiple biomarkers because the change in the level of a single biomarker is often not peculiar to them [3–6] . Cancer is another example that a set of biomarkers need to be analyzed for accurate diagnosis even with biopsy results [7, 8] . Furthermore, the deconvolution of complex interacting networks for in‐depth understanding of a specific biological process often requires simultaneous detection of various biomarkers.…”