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

Sultana Mehbuba Hossain,Syafiq Asnawi Zainal Abidin,Ezharul Hoque Chowdhury

doi:10.3390/cancers12010161

Sultana Mehbuba Hossain, Syafiq Asnawi Zainal Abidin + Show 1 more

Open Access

https://doi.org/10.3390/cancers12010161

Copy DOI

Journal: Cancers	Publication Date: Jan 9, 2020
Citations: 6	License type: CC BY 4.0

Affiliation: Monash University Malaysia

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.

Highlights

Breast cancer is the most common cancer in women [1] and the second leading cause of global cancer death after lung cancer [2]
We examined carbonate apatite (CA), citrate-modified CA (CMCA), and α-ketoglutaric acid-modified CA (α-KAMCA) NPs for in vivo tumor regression, biodistribution, plasma concentration, and toxicology study depending on their promising in vitro results, especially through a cytotoxicity assay in the 4T1 cell line
Action depends on the high drug binding affinity ensure to improved bioavailability, decreased clearance, and increased with theenhanced minimalsolubility amount ofleading materials needed for administration

Summary

Introduction

Breast cancer is the most common cancer in women [1] and the second leading cause of global cancer death after lung cancer [2]. Cancers 2020, 12, 161 whereas cyclophosphamide (CYP) is highly reported as a neoadjuvant therapy with an anthracycline, microtubule stabilizers, or platinum agents to achieve improved efficacy and maximum benefits [6,7,8] In these therapies, CYP was administered to the patients in a high dose of almost 600 mg/m2 [8] to exert its clinical efficacy [9,10], leading to nausea, vomiting, neutropenia [8], and cardiac toxicity [11]. The alkylating agent CYP is a prodrug which is metabolized in the liver by cytochrome P450, producing pharmacologically stable toxic metabolites—acrolein and phosphoramide mustard These metabolites passively enter into the cell and attach to the guanine base of DNA, which hinders DNA replication by establishing intrastrand and interstrand DNA cross-linking [11,12]. CYP is a widely used chemotherapeutic in cancer treatment due to its direct cytotoxic effect on cancer cells with an immunoregulatory response [13] depending on the dose of the drug, as shown in a mouse model, ranging from 20–200 mg/kg [14,15,16]

Methods

Results

Conclusion