Lipid-Coated CaCO3 Nanoparticles as Tumor Acidity Responsive Nanocarriers

Chemotherapy is a type of anti-cancer drug treatment. These drugs work by killing cancer cells. Chemotherapy in cancer has merged the disease course from a terminal and catastrophic result in merely all cases to a treatable and sometimes curable illness through the right approach. The goal of chemotherapy is to inhibit cell proliferation and tumor multiplication, thus avoiding invasion and metastasis. But this results in toxic effects of chemotherapy due to the effect on normal cells as well. Traditional chemotherapy agents primarily affect either macromolecular synthesis and function of neoplastic cells by interfering with DNA, RNA, or proteins synthesis or affecting the appropriate functioning of the preformed molecule. When interference in macromolecular synthesis or function is sufficient, it leads to cell death due to the chemotherapeutic agent’s direct effect or by triggering apoptosis. Combination chemotherapy is a common choice to produce adequate responses as well. They appear to prevent the development of resistant clones by promoting cytotoxicity in resting and dividing cells. The development of smart drug delivery nanocarriers for tumor-targeted delivery and controllable release of therapeutic agents is appealing to achieve effective cancer chemotherapy.

In a new study published in ACS Applied Bio Materials, Yuejuan Xu, Chunjie Wang, Fangrong Shen, Ziliang Dong, Yu Hao, Youguo Chen, Zhuang Liu, and led by Professor Liangzhu Feng from Soochow University developed a new type of liposomal CaCO₃ with versatile drug-loading capacities as promising nanoscale drug delivery system to enable tumor acidity responsive drug delivery. They showed that liposomal CaCO₃ could enable simultaneous encapsulation of more than one small-molecule chemotherapeutics (e.g., DOX, Oxa (IV)-DSPE) with distinct physicochemical properties.

The research team observed that doxorubicin could be efficiently loaded into the prepared CaCO₃ nanoparticles at a high loading efficacy of 76.5% by simple mixing. As recorded by the UV-vis-NIR spectrometer, they observed typical absorption peaks of DOX ranging from 400 to 550 nm in the spectrum of DOX-Pt(IV)-CaCO₃-PEG, indicating the successful encapsulation of doxorubicin. The research team found that the size of DOXPt(IV)-CaCO₃-PEG exhibited negligible fluctuations in these solutions throughout a 24 h measurement, indicating excellent physiological stability. Results further demonstrated that DOX-Pt(IV)-CaCO₃-PEG showed excellent pH-dependent dissociation and drug release behaviors. Further they unveiled that doxorubicin fluorescence inside these 4T1 murine breast cancer cells incubated with DOX-Pt(IV)-CaCO₃-PEG was first observed in the cytosol and then gradually accumulated in the nucleus with the extension of incubation time. Results further demonstrated that the treatment of DOX-Pt(IV)-CaCO₃-PEG showed superior cytotoxicity to 4T1 cells in comparison with the treatment of plain Pt(IV)-CaCO₃-PEG under the same experimental conditions. It was observed that DOX-Pt(IV)-CaCO₃-PEG showed slightly enhanced cytotoxicity to 4T1 cells in comparison with free DOX, while the treatment of plain CaCO₃-PEG exhibited negligible influence on the viability of 4T1 cells. DOX-Pt(IV)-CaCO₃-PEG showed significantly reduced cytotoxicity to two normal cell lines of human umbilical vein endothelial cells (HUVEC) and NIH-3T3, indicating a good safety profile.

The authors further found that the DiR fluorescence signal of the tumor region on these mice intravenously injected with such DiR-labeled DOX-Pt(IV)-CaCO₃-PEG gradually increased throughout a 24 h observation. Results showed that the blood circulation profiles of both DOX-Pt(IV)-CaCO₃-PEG and free DOX followed a two compartment model. Results further indicated that DOX-Pt(IV)-CaCO₃-PEG exhibited a significantly prolonged blood circulation time of DOX, thereby improving its tumor homing capacity via the passive enhanced permeability and retention (EPR) effect. Further treatment with DOX-Pt(IV)-CaCO₃-PEG was found to be the most effective in suppressing tumor growth while the treatments with Pt(IV)-CaCO₃-PEG or DOX-CaCO₃-PEG only moderately suppress tumor growth. Results demonstrated the superior therapeutic efficacy of DOX-Pt(IV)-CaCO₃-PEG, which is more effective than that for single cancer chemotherapy.

In conclusion, Professor Liangzhu Feng and colleagues developed a type of liposomal CaCO₃ with versatile drug-loading capacities as promising NDDSs to enable tumor acidity responsive drug delivery. Study highlights that liposomal CaCO₃ is a robust and biocompatible platform for preparing pH-responsive drug delivery systems, due to its multifaceted drug loading capacity, and thus is promising for potential clinical translation.

At last, Professor Liangzhu Feng said that such liposomal CaCO₃ could also remarkably promote the deep tissue penetration of their loaded therapeutics inside solid tumors attributing to their pH-responsive dissociation property. Meanwhile, the tumor accumulated liposomal CaCO₃ could work as an efficient proton sponge to neutralize the acidic tumor microenvironment, a hostile feature of most solid tumors, and thereby potentiate other cancer treatments based on their successive studies.