Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment

Abstract

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness of silica-based carriers to spontaneous drug release. Calcium carbonate (CaCO₃) is an emerging alternative, being an easily available, cost-effective, and biocompatible material with high porosity and surface reactivity, which makes it an attractive choice for targeted drug delivery. CaCO₃ particles are used in this field in the form of either bare CaCO₃ microbeads or core/shell microparticles representing polymer-coated CaCO₃ cores. In addition, they serve as removable templates for obtaining hollow polymer microcapsules. Each of these types of particles has its specific advantages in terms of biomedical applications. CaCO₃ microbeads are primarily used due to their capacity for carrying pharmaceutics, whereas core/shell systems ensure better protection of the drug-loaded core from the environment. Hollow polymer capsules are particularly attractive because they can encapsulate large amounts of pharmaceutical agents and can be so designed as to release their contents in the target site in response to specific stimuli. This review focuses first on the chemistry of the CaCO₃ cores, core/shell microbeads, and polymer microcapsules. Then, systems using these structures for the delivery of therapeutic agents, including drugs, proteins, and DNA, are outlined. The results of the systematic analysis of available data are presented. They show that the encapsulation of various therapeutic agents in CaCO₃-based microbeads or polymer microcapsules is a promising technique of drug delivery, especially in cancer therapy, enhancing drug bioavailability and specific targeting of cancer cells while reducing side effects. To date, research in CaCO₃-based microparticles and polymer microcapsules assembled on CaCO₃ templates has mainly dealt with their properties in vitro, whereas their in vivo behavior still remains poorly studied. However, the enormous potential of these highly biocompatible carriers for in vivo applications is undoubted. This last issue is addressed in depth in the Conclusions and Outlook sections of the review.

Keywords: anticancer treatment; calcium carbonate; core/shell structures; microcapsules; microparticles; targeted delivery.

Figure 1

Spherical CaCO₃-based microparticles for targeted cancer therapy: (a) a CaCO₃ core-only microparticle; (b) a CaCO₃ core/shell microparticle; (c) a polyelectrolyte shell-only microcapsule without a core.

Figure 2

(1) Preparation of CaCO₃/HA/Glu MHSs, efficient loading of DOX, targeted delivery, specific internalization, and significant inhibition of cancer cells. (2) In vitro release profiles of CaCO₃/HA/Glu/DOX under different pH. Data represent the mean ± S.D.; n = 3. (3) Cytotoxic effects of free DOX, CaCO3/HA/Glu, and CaCO³/HA/Glu/DOX on HeLa cells after 3 d treatment. Data represent the mean ± S.D.; n = 3. Abbreviations: HA, hyaluronate; Glu, glutamate; MHSs, mesoporous hollow spheres; DOX, doxorubicin. Adapted with permission from Guo, Y. et al., J. Coll. Interf. Sci.; published by Elsevier, 2017 [52].

Figure 3

Summary of data on fabrication of porous CaCO₃ core-only and CaCO₃ core/shell microparticles. On the left: the pore size diameters for differently fabricated CaCO₃ cores are shown to be in the range of 2–50 nm [21], 5–30 nm [43], 10–60 nm [44] or 20–500 nm [49]. On the right: the shells on the CaCO₃ cores may be fabricated by the deposition of different polymers such as poly-L-ornithine/fucoidan [56]; poly(ethylene glycol)/oleic acid [57]; hyaluronic acid/glutamate [52]; hyaluronic acid/tannic acid [60]; ovalbumin/platelet lysate [53]; poly(diallyldimethylammonium chloride)/poly(sodium 4-styrenesulfonate) [58]; hyaluronic acid [50]; polylactic acid [61]; poly(acrylic acid) [62].

Figure 4

(1) Assembly schematic: the preparation of CaCO₃-HMPs through self-assembly of two oppositely charged polyelectrolytes, PDDA and PSS, on the surface of yeast cells, as dual templates for drug loading and release. (2) Cytotoxicity tests of CaCO₃-HMPs, DOX, and the CaCO₃-HMPs-DOX drug-delivery system (* p < 0.05, *** p < 0.001); (3) Cumulative release curve of DOX in different environments: (a) pH = 4.8 and (b) pH = 7. Abbreviations: HMPs, herbal medicinal products; PDDA, poly(diallyldimethylammonium chloride); PSS, poly(sodium 4-styrenesulfonate); DOX, doxorubicin. Reproduced with permission from Wei, Y., et al. Coll. Surf. B Biointerf.; published by Elsevier, 2021 [58].

Figure 5

Summary of data on fabrication of microcapsules initially based on the CaCO₃ microparticles [18,20,22,29,32,36,57,64,65,67,68,69,70,72,73,75,76,77,78,79,81,89].

Figure 6

(1) Scheme of the stepwise capsule assembly, compaction, and loading. (2) Lung cancer cell viability in the presence of 20 μM free or encapsulated gemcitabine; MTT assay at the indicated time points. (3) Number of cells in the lungs, liver, kidney, and spleen with internalized Cy5-labeled capsules relative to the total amount of cells in the respective organs 24 and 72 h after intravenous injection of PMC. Abbreviation: PMC, polymeric multilayer capsules. Adapted with permission from Novoselova, M. V., et al. ACS Appl. Mater. Interfaces; published by American Chemical Society, 2020 [70].