Liposomes of Quantum Dots Configured for ... - ACS Publications

Jerusalem 9112001, Israel. (P) +972-2-6758658; (F) +972-2-6757126 [email protected]. Page 1 of 26. ACS Paragon Plus Environment. Nano Letters. ...
0 downloads 0 Views 994KB Size
Subscriber access provided by ECU Libraries

Communication

Liposomes of Quantum Dots Configured for Passive and Active Delivery to Tumor Tissue Gil Aizik, Nir Waiskopf, Majd Agbaria, Meital Ben-David-Naim, Yael Levi-Kalisman, Amit Shahar, Uri Banin, and Gershon Golomb Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b01027 • Publication Date (Web): 19 Aug 2019 Downloaded from pubs.acs.org on August 20, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Nano Letters

Liposomes of Quantum Dots Configured for Passive and Active Delivery to Tumor Tissue

Gil Aizik1, Nir Waiskopf2, Majd Agbaria1, Meital Ben-David-Naim1, Yael Levi-Kalisman3,4, Amit Shahar1, Uri Banin2,4, Gershon Golomb*1,4

1Institute

for Drug Research, School of Pharmacy, the Faculty of Medicine, 2Institute of

Chemistry, and 3Institute of Life Sciences, Faculty of Life Sciences, and 4The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem, Israel.

*Corresponding Author: Prof. Gershon Golomb (ORCID No. 0000-0002-7369-9831) Institute for Drug Research School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem 12065 Ein Kerem Medical Center, Jerusalem 9112001, Israel (P) +972-2-6758658; (F) +972-2-6757126 [email protected]

ACS Paragon Plus Environment

1

Nano Letters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

Abstract The majority of developed and approved anti-cancer nanomedicines have been designed to exploit the dogma of enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor’s blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species, and its poor translation to human cancer therapy. In order to facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive (‘stealth’ NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively-charged) properties by differing in their lipids composition, membrane PEGylation, and charge (positively, negatively-, neutrally-charged). The various physicochemical parameters affecting entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by fluorescence intensity and Cd analyses. Following treatment of animals (intact and mammary carcinoma bearing mice) with disparate formulations of LipQDs (differing by their lipids composition, neutrally- and positively-charged surface, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nano-sized liposomal formulations, prepared by a new facile method, have superior structural and optical stability, and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs. Key words: Quantum dots, liposomes, Enhanced Permeability and Retention (EPR), active delivery, monocytes/macrophages, mammary carcinoma.

ACS Paragon Plus Environment

2

Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Nano Letters

Nanotechnology holds great potential to be further explored and utilized as a multifunctional platform for a wide range of biological and engineering applications in cancer, including imaging and therapy.1, 2 The essence of nanomedicine is to improve delivery of the drug/imaging agent to the tumor tissue, thus increasing the therapeutic index by modifying the biodistribution of nanoparticles (NPs). This approach relies primarily on the enhanced permeability and retention (EPR) effect, termed ‘passive delivery’, a unidirectional extravasation from the blood and into the tumor. As first described by Maeda et. al. in 1986, the leaky vascular structure in tumors allows extravasation of NPs, and their retention is attributed to the lack of lymphatic drainage in the tumor.3, 4 Doxil®, the first FDA approved liposomal preparation, used for the treatment of Kaposi's sarcoma, multiple myeloma and ovarian cancer, employs the EPR effect.5 Indeed, of the 11 therapeutic molecules approved for cancer therapy based on the EPR effect, 8 are liposomal formulations. Moreover, the majority of cancer nanomedicines have been designed to exploit the EPR effect (passive delivery), with a small subset of nanomedicines seeking to increase NPs accumulation in the tumor tissue with ligand-mediated targeting.6-10 Although the EPR effect has become the major mechanism in developing anti-cancer nanomedicines,3-5, 10-15 it has been under scrutiny recently due to disappointing therapeutic efficacy, and limited clinical success.5, 10-14, 16 In order to facilitate the EPR effect, systemically injected liposomes (as well as macromolecules and other NPs) should overcome the first and foremost obstacle of foreign particulate matter in the blood- rapid recognition and elimination by the mononuclear phagocyte system (MPS).17 The MPS consists of phagocytic cells, blood monocytes, and tissue monocytes and macrophages (mainly in the spleen and liver), which rapidly recognize and eliminate

ACS Paragon Plus Environment

3

Nano Letters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 26

particulate matter. The major techniques for conferring ‘stealth’ properties enabling prolonged residence-time in the blood are size (12-fold higher than that resulting from Lip(+)QDs treatment; Figure 2a) consists of free circulating pegLip(±)QDs, as evidenced from the ~3-fold lower number of QDs-containing monocytes (5.1% vs. 16.7%; Figure 2b). In stark contrast to the liposomal formulations, free QDs administration was characterized

Figure 2. QDs biodistribution in the blood of intact mice 4 h after IV administration of QDs (200 µl of 250 nM). a) Whole blood Cd levels; b) Circulating monocytes containing QDs (% of total monocytes; FACS analysis), and illustrated schematically in (c). Note that only Lip(+)QDs treatment exhibited significant uptake by circulating monocytes (for other cell populations see Figure S6). Despite the high blood levels of pegLip(±)QDs, only a minor fraction of QDs-containing monocytes was detected, as expected from PEGylated NPs. n=4 in each group; **p