Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

Chanchal Kiran Thakur; Rabin Neupane; Chandrabose Karthikeyan; Charles R Ashby Jr; R Jayachandra Babu; Sai H S Boddu; Amit K Tiwari; Narayana Subbiah Hari Narayana Moorthy

doi:10.3390/molecules27217461

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

Molecules. 2022 Nov 2;27(21):7461. doi: 10.3390/molecules27217461.

Authors

Chanchal Kiran Thakur¹, Rabin Neupane², Chandrabose Karthikeyan¹, Charles R Ashby Jr³, R Jayachandra Babu⁴, Sai H S Boddu^{5

6}, Amit K Tiwari^{2

5

7}, Narayana Subbiah Hari Narayana Moorthy¹

Affiliations

¹ Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak 84887, Madhya Pradesh, India.
² Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
³ Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, NY 11431, USA.
⁴ Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, Ajman University, Ajman P.O. Box 346, United Arab Emirates.
⁶ Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates.
⁷ Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Abstract

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug-loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin-loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.

Keywords: breast cancer; carbohydrate; cellular uptake; drug delivery; lysinated MWCNTs; multiwalled carbon nanotubes.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Breast Neoplasms* / drug therapy
Doxorubicin / chemistry
Doxorubicin / pharmacology
Drug Delivery Systems / methods
Female
Humans
Ligands
Nanotubes, Carbon* / chemistry
Spectroscopy, Fourier Transform Infrared
Tumor Microenvironment

Substances

Nanotubes, Carbon
Ligands
Doxorubicin
Antineoplastic Agents

Grants and funding

This research was partially supported in part by the Cancer Cure Funds (2402445), Susan G. Komen Breast Cancer Foundation (CCR18548498) and Department of Defense (1W81XWH-21-1-0053) (to A.K.T.). The views expressed in this article are those of the authors and may not reflect the official policy or position of the Department of the Army, Department of Defense or the U.S. Government.