Abstract
B-cell lymphoma cells depend upon cholesterol to maintain pro-proliferation and pro-survival signaling via the B-cell receptor. Targeted cholesterol depletion of lymphoma cells is an attractive therapeutic strategy. We report here high-density lipoprotein mimicking magnetic nanostructures (HDL-MNSs) that can bind to the high-affinity HDL receptor, scavenger receptor type B1 (SR-B1), and interfere with cholesterol flux mechanisms in SR-B1 receptor positive lymphoma cells, causing cellular cholesterol depletion. In addition, the MNS core can be utilized for its ability to generate heat under an external radio frequency field. The thermal activation of MNS can lead to both innate and adaptive antitumor immune responses by inducing the expression of heat shock proteins that lead to activation of antigen presenting cells and finally lymphocyte trafficking. In the present study, we demonstrate SR-B1 receptor mediated binding and cellular uptake of HDL-MNS and prevention of phagolysosome formation by transmission electron microscopy, fluorescence microscopy, and ICP-MS analysis. The combinational therapeutics of cholesterol depletion and thermal activation significantly improves therapeutic efficacy in SR-B1 expressing lymphoma cells. HDL-MNS reduces the T2 relaxation time under magnetic resonance imaging (MRI) more effectively compared with a commercially available contrast agent, and the specificity of HDL-MNS toward the SR-B1 receptor leads to differential contrast between SR-B1 positive and negative cells suggesting its utility in diagnostic imaging. Overall, we have demonstrated that HDL-MNSs have cell specific targeting efficiency, can modulate cholesterol efflux, can induce thermal activation mediated antitumor immune response, and possess high contrast under MRI, making it a promising theranostic platform in lymphoma.
Original language | English (US) |
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Pages (from-to) | 10301-10311 |
Number of pages | 11 |
Journal | ACS nano |
Volume | 13 |
Issue number | 9 |
DOIs | |
State | Published - Sep 24 2019 |
Funding
A.S., V.N., J.S.R., S.-R.R., C.S.T., and V.P.D. gratefully acknowledge support from the NTU-NU Institute for NanoMedicine located at the International Institute for Nanotechnology, Northwestern University, USA, and the Nanyang Technological University, Singapore. J.S.R. was supported by a National Institute of Health/National Heart, Lung and Blood Institute (NIH/NHLBI) Vascular Surgery Scientist Training Grant (T32HL094293). This work made use of the CAMI, BIF, QBIC, NU-HTA, and CTI of Northwestern University and EPIC and Keck-II facilities of Northwestern University’s NU ANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; the State of Illinois, through the IIN. The methodology is partially based on research sponsored by the Air Force Research laboratory under agreement number FA8650-15-2-5518. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of Air Force Research Laboratory or the U.S. Government. Authors thank Dr Sijia Yi for her help during the T cell activation study.
Keywords
- SR-B1 receptor
- antitumor immune response
- high-density lipoprotein
- lymphoma
- magnetic nanostructure
- thermal activation
ASJC Scopus subject areas
- General Materials Science
- General Engineering
- General Physics and Astronomy