Krebs Cycle Intermediate-Modified Carbonate Apatite Nanoparticles Drastically Reduce Mouse Tumor Burden and Toxicity by Restricting Broad Tissue Distribution of Anticancer Drugs

Abstract

The morphology, size, and surface area of nanoparticles (NPs), with the existence of functional groups on their surface, contribute to the drug binding affinity, distribution of the payload in different organs, and targeting of a particular tumor for exerting effective antitumor activity in vivo. However, the inherent chemical structure of NPs causing unpredictable biodistribution with a toxic outcome still poses a serious challenge in clinical chemotherapy. In this study, carbonate apatite (CA), citrate-modified CA (CMCA) NPs, and α-ketoglutaric acid-modified CA (α-KAMCA) NPs were employed as carriers of anticancer drugs for antitumor, pharmacokinetic, and toxicological analysis in a murine breast cancer model. The results demonstrated almost five-fold enhanced tumor regression in the cyclophosphamide (CYP)-loaded α-KAMCA NP-treated group compared to the group treated with CYP only. Also, NPs promoted much higher drug accumulation in blood and tumor in comparison with the drug injected without a carrier. In addition, doxorubicin (DOX)-loaded NPs exhibited less accumulation in the heart, indicating less potential myocardial toxicity in mice compared to free DOX. Our findings, thus, conclude that CA, CMCA, and α-KAMCA NPs extended the circulation half-life and enhanced the anticancer effect with reduced toxicity of conventional chemotherapeutics in healthy organs, signifying that they are promising drug delivery devices in breast cancer treatment.

Silicon–Gold Nanoparticles Affect Wharton’s Jelly Phenotype and Secretome during Tri-Lineage Differentiation

“…Recent advances in nanotherapeutics provide diverse groups of synthetic nanoparticles (NPs) and other types of nanomaterials. Intravenous injection of NPs results in their accumulation in the liver [1][2][3], damaging epithelial and Kupfer's cells. Liver as well as other organ regeneration depends on the functional potential of tissue stem cells.…”

Delivery of siRNAs Against Selective Ion Channels and Transporter Genes Using Hyaluronic Acid-coupled Carbonate Apatite Nanoparticles Synergistically Inhibits Growth and Survival of Breast Cancer Cells

“…The PT-IR spectra 59 in the Figure 10 has demonstrated the formation of hybrid carbonate apatite particles by identifying carbonate in the apatite material, as evident from the peaks between 1410 and 1540 cm −1 and at approximately 880 cm −1 and phosphate in the apatite, as shown by the peaks at 1000–1100 cm −1 , 60 as well as 1600–1650 cm −1 for O-H, C=0, N-H present in hyaluronic acid. 62 The broad and strong peaks at 1600–1650 cm −1 , confirmed the existence of the numerous carboxyl and hydroxyl groups in HA.…”

“…They also ensure favorable pharmacokinetic profiles, induce no remarkable cytotoxicity, facilitate promising tumor uptake and last, but not the least, do rapid cytosolic release of the used siRNA(s). 60 , 63–65

Figure 13 Effects of IV (intravenous) administered nanoparticles and siRNA loaded nanoparticles on tumor regression. Tumor measurement by using a digital Vernier calliper (values are significant * p <0.05, very significant ** p <0.01, and highly significant *** p <0.001).

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“…There was a significant siRNA accumulation for both formulations in the off-target organs, such as brain, heart and lungs 24 h after the intravenous administration. 60 , 66

Figure 15 Biodistribution studies of plain CA NPs after 24 h.

Figure 16 Biodistribution studies of hybrid HA- CA NPs after 24 h.

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Carbonate Apatite and Hydroxyapatite Formulated with Minimal Ingredients to Deliver SiRNA into Breast Cancer Cells In Vitro and In Vivo

“…In terms of chemical composition, this is a derivative of HA formed by substituting some phosphate ions with carbonate ions with a final molecular formula Ca 10 (PO 4 ) 6−X (CO 3 ) X (OH) 2 . The easy fabrication method takes only 30 min at 37 • C. CA NPs have been used successfully in our lab for in vitro and in vivo delivery of anticancer drugs, such as taxanes (paclitaxel and docetaxel), doxorubicin, cisplatin, gemcitabine, siRNAs against genes of growth factors, antiapoptotic proteins, cell adhesion molecules and plasmids carrying genes p21 and p53 in an animal model of breast cancer [12][13][14][15][16][17][18][19][20]. Upon cellular internalization by endocytosis, particles are thought to be rapidly dissolved into constituent ions such as Ca 2+ , PO 4 3− and HCO 3 − in endosomal acidic pH, leading to an increase in osmotic pressure across the endosomal membrane, consequential water entry into the endosome, swelling and rupturing of the endosome, and ultimately releasing the siRNA, plasmid or drug in the cytoplasm.…”