Adenosine triphosphate (ATP) is an important transmitter that mediates various biological effects via purinergic receptors (P2 receptors) in cancer. We investigated the antitumor activity of ATP-decorated and doxorubicin (DOX)-loaded mesoporous silica with biomineralization of calcium carbonate against a highly aggressive and metastatic murine lymphoma called Dalton's lymphoma (DL). Our results suggest that this nanocomposite has unique effects with respect to the morphology and properties of calcium carbonate on the surface of the nanoparticle. DOX in the nanoparticles was prevented from quick release via the interactions of the phosphate group present on ATP and calcium carbonate. This construct is significantly tumoricidal against parental and DOX-resistant DL cells and is thus a promising candidate for applications in drug delivery. The composite nanomaterial has excellent biocompatibility with higher uptake and acts via the participation of the purinergic receptor P2X7. The nanocomposite induces significantly higher apoptosis in tumor cells compared with DOX alone. Treatment of DL-bearing mice with the construct significantly reduces tumor burden, in addition to augmenting the lifespan of tumor-bearing mice as demonstrated by a sustained healthy life of the animals and improved histopathological parameters.

Pepsin, a digestive enzyme, plays an important role in the metabolism of protein products in the stomach. The pH is regarded as the most pivotal criteria in appraising the pepsin’s enzymatic activity. Pepsin is idle at the physiological pH (7.4) but dynamic in the acidic environments of the stomach (pH 2.0–4.0). Inspired by such pH regulatory actions, we have used pepsin as an enhancer, which is attached to silica nanoparticles for the doxorubicin release in the acidic tumor environment. Pepsin enzyme is transitional between the doxorubicin loaded silica nanoparticles and the biotin–avidin cap system, which intercedes the pores. The formed nanoplatform is poised at the physiological pH. However, when switched to low pH simulated conditions, the pepsin become vibrant and cleaves the avidin, rendering the clearance of the path for the diffusion of the drug. This design strategy augmented the drug bioavailability deep inside the solid tumor with enhanced uptake and apoptosis of the tumor cells in experimental lymphoma.

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