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Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (∼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo, the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment.

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The acidic tumor environment has emerged as a crucial factor influencing the metastatic potential of cancer. We investigated the effect of an acidic environment on the acquisition of metastatic properties in MCF7 breast cancer cells and explored the inhibitory effects of gallic acid. Prolonged exposure to acidic culture conditions (over 12 weeks at pH 6.4) induced the acquisition of migratory and invasive properties in MCF7 cells, accompanied by increased expression of Matrix Metalloproteinase 2 and 9 (MMP2 and MMP9, respectively), together with alterations in E-cadherin, vimentin, and epithelial-to-mesenchymal transition markers. Gallic acid effectively inhibited the survival of acidity-adapted MCF7 (MCF7-6.4/12w) cells at high concentrations (>30 µM) and reduced metastatic characteristics induced by acidic conditions at low concentration ranges (5-20 µM). Moreover, gallic acid suppressed the PI3K/Akt pathway and the nuclear accumulation of ß-catenin, which were elevated in MCF7-6.4/12w cells. These findings highlight the potential of gallic acid as a promising therapeutic agent for metastatic traits in breast cancer cells under acidic conditions.

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Carbohydrate-lectin interactions and glycol-molecule-driven self-assembly are powerful yet challenging strategies to create supramolecular nanostructures for biomedical applications. Herein, we develop a modular approach of micellization with a small molecular mannosylated-calix[4]arene synthetic core, CA4-Man3, to generate nano-micelles, CA4-Man3-NPs, which can target cancer cell surface receptors and facilitate the delivery of hydrophobic cargo. The oligomeric nature of the calix[4]arene enables the dynamic self-assembly of calix[4]arene (CA4), where an amphiphile, functionalized with mannose units (CA-glycoconjugates) in the upper rim and alkylated lower rim, afforded the CA4-Man3-NPs in a controllable manner. The presence of thiourea units between calixarene and tri-mannose moiety facilitated the formation of a stable core with bidentate hydrogen bonds, which in turn promoted mannose receptor targeted uptake and helped in the intracellular pH-responsive release of antineoplastic doxorubicin (Dox). Physiochemical features including the stability of the nanomicelle could circumvent the undesirable leakage of the cargoes, ensuring maximum therapeutic output with minimum off-targeted toxicity. Most importantly, surface-enhanced Raman scattering (SERS) was utilized for the first time to evaluate the critical micelle concentration during the formation, cellular uptake and intracellular drug release. The present study not only provides an architectural design of a new class of organic small molecular nanomicelles but also unveils a robust self-assembly approach that paves the way for the delivery of a wide range of hydrophobic chemotherapeutic drugs.

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Vacuolar H+-ATPase (V-ATPase) serves a key role in adjusting and maintaining the intracellular pH, as well as in regulating the drug resistance of tumor cells. In recent years, the expression level of V-ATPase has been considered to be able to predict the sensitivity of breast cancer cells to chemotherapy drugs. Cluster of differentiation 147 (CD147) is known to serve a key role in the development and progression of breast cancer. The present study aimed to identify the role CD147 and V-ATPase in chemoresistance in breast cancer, and to characterize the regulation of CD147 on V-ATPase. Firstly, the expression levels of CD147 and V-ATPase were detected in chemotherapy-resistance breast cancer samples. It was demonstrated that V-ATPase was highly expressed in chemotherapy-resistance breast cancer samples, and that its expression was correlated with CD147 expression. Subsequently, MCF-7 and MDA-MB-231 cells were used to study the regulatory effect of CD147 on the expression and function of V-ATPase. Gene transfection or small interfering RNA transfection were used to control the expression of CD147 in the two cell lines. The results revealed that the overexpression of CD147 increased the expression of V-ATPase in MCF-7 cells, whereas CD147 knockdown decreased V-ATPase expression in MDA-MB-231 cells. It was also observed that CD147 affected the V-ATPase activity, regulating the transmembrane pH gradient of cancer cells. These results demonstrated that CD147 was associated with the sensitivity of chemotherapeutic drugs of epirubicin and docetaxel, while pantoprazole was able to partially reverse the CD147-mediated chemoresistance in breast cancer. Therefore, the current study provided a possible mechanism for further examination of drug resistance in breast cancer.