PEGylated Liposomes Remotely Loaded with the Combination of Doxorubicin, Quinine, and Indocyanine Green Enable Successful Treatment of Multidrug-Resistant Tumors

Emma Grabarnick (Portnoy),Alexander V Andriyanov,Yechezkel Barenholz,Hadas Han,Sara Eyal

doi:10.3390/pharmaceutics13122181

Emma Grabarnick (Portnoy), Alexander V Andriyanov + Show 3 more

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https://doi.org/10.3390/pharmaceutics13122181

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Journal: Pharmaceutics	Publication Date: Dec 17, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: Hebrew University of Jerusalem

Abstract

Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance in vivo. The present study explored the therapeutic potential of combined treatment with liposomal doxorubicin, P-gp inhibitor quinine, and the photodynamic therapy (PDT) using indocyanine green (ICG) in the adenocarcinoma drug-resistant tumor model. Liposomes were actively co-remotely loaded with doxorubicin and quinine, and ICG was passively adsorbed. The liposomes were characterized by differential scanning calorimetry (DSC) and cryogenic transmission microscopy (Cryo-TEM). We found that quinine impaired the crystalline structure of doxorubicin. In vitro, treatment with single agents themselves was insufficient to inhibit the growth of HT-29 MDR1 cells. However, pegylated liposomal doxorubicin and quinine (PLDQ) significantly diminished HT-29 MDR1 cell survival. Furthermore, survival inhibition intensified by the addition of ICG to the PLDQ (ICG + PLDQ). In vivo, ICG + PLDQ significantly decreased tumor growth when combined with tumor irradiation with NIR light (** p < 0.01). ICG + PLDQ + irradiation was superior to single treatments or combinational treatments without irradiation. These findings suggest that ICG + PLDQ can overcome P-gp-mediated MDR in cancer cells.

Highlights

Despite advances in chemotherapies against cancer, multidrug resistance (MDR) still hampers positive therapeutic outcomes [1]
Cryo-TEM revealed (Figure 1b) that no crystal was formed in the intra-liposomes of liposomes remotely loaded with quinine alone (Lip + Q) and with differential scanning calorimetry (DSC) thermograms (Figure 1e)
Quinine compromised the crystalline structure of doxorubicin sulfate at the intra-liposomes aqueous phase in pegylated liposomal doxorubicin and quinine (PLDQ)

Summary

Introduction

Despite advances in chemotherapies against cancer, multidrug resistance (MDR) still hampers positive therapeutic outcomes [1]. MDR, characterized by cross-resistance to multiple functionally and structurally unrelated drugs [2], often caused by the treatment [3]. But may be intrinsic to many tumor types. P-glycoprotein (P-gp/ABCB1), a member of the ATP-binding cassette superfamily of transporters (ABC). P-gp is expressed in many cancer types [4], and its presence correlates with poor prognosis [5,6,7]. Among P-gp substrates, there is a broad range of medications, including anti-cancer drugs such as doxorubicin and paclitaxel [8,9]. Drug-drug interactions, toxicity, and design have led to the failure of most clinical trials [13,14]

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