(675d) Nanoparticle Hitchhiked T Cells for Targeted Drug Delivery

Authors: 
Abedin, M. R., Missouri University of Science and Technology
Liu, Y., Mallinckrodt Institute of Radiology, Washington University School of Medicine
Barua, S., Missouri University of Science and Technology

Abedin, Muhammad (S&T-Student) Normal Abedin, Muhammad (S&T-Student) 2 2498 2019-04-12T03:37:00Z 2019-04-12T03:37:00Z 1 497 2837 Missouri University of Science and Technology 23 6 3328 15.00

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text-align:center;line-height:19.2pt;background:white">Biomaterials (08B 05)

text-align:center;line-height:19.2pt;background:white"> normal"> " times new roman>Nanoparticle Hitchhiked
T Cells for Targeted Drug Delivery

text-align:center;line-height:19.2pt;background:white">Muhammad Raisul Abedina, Yongjian Liub, Sutapa Baruaa,1

text-align:center;line-height:19.2pt;background:white">a Department of Chemical and Biochemical
Engineering, Missouri University of Science and Technology,

text-align:center;line-height:19.2pt;background:white">Rolla, MO-65409

text-align:center;line-height:19.2pt;background:white"> b Mallinckrodt Institute of Radiology, Washington
University School of Medicine, Washington University    in St. Louis, St. Louis, MO-63110

text-align:center;line-height:19.2pt;background:white">1 10.0pt;font-family:" times new roman color:>Corresponding Author: Email: baruas@mst.edu

text-align:center;line-height:19.2pt;background:white">

normal">Abstract

normal">

justify"> line-height:107%;font-family:" times new roman>Objective

mso-add-space:auto;text-align:justify;line-height:normal">We explore a
combinatorial approach in exploiting the specificity of antibody conjugated
drug nanorods with the direction of polyclonal T cells for breast cancer
therapy. We hypothesize that the attachment of Trastuzumab-conjugated
paclitaxel drug nanorods to natural T cells will enhance their circulation time
and will have better accessibility to the complex tumor microenvironment. The
cellular vehicle could substantially alter their anti-tumoral
efficacy and hence be an efficient biocompatible system for therapeutic drug
delivery.

mso-add-space:auto;text-align:justify;line-height:normal">

justify"> line-height:107%;font-family:" times new roman>Introduction

auto;text-align:justify;line-height:normal"> font-family:" times new roman>Our current study aims to take a
combinatorial approach of immunotherapies, and targeted drug NPs for efficient delivery of therapeutic payloads to
the breast cancer site, and expand therapeutic benefits. Major
limitations of the current nano drug delivery vehicles are inefficient
transport of drug to the tumor site, uncontrolled nanoparticle-biomolecule
interaction at the extra cellular matrix, and intracellular lysosomal or
phagolysosomal degradation of the nanoparticle.
Moreover, the majority of the designed
nano drug vehicles accumulate in the vicinity of the off target cells or
tissues resulting in off target toxicity or might be eliminated by the residing
macrophages in the organs like liver and spleens. Here, we propose
an alternative strategy that makes use of the ability of natural immune T cells
to circulate and target breast cancer cells for the effective delivery of drug
NPs. Specifically, it is proposed to anchor Trastuzumab conjugated paclitaxel
drug nanorods to the surface of patient derived T cells as a means of avoiding
the reticuloendothelial system (RES) clearance.

justify">

justify"> line-height:107%;font-family:" times new roman>Materials and Methods

justify"> 107%;font-family:" times new roman>Paclitaxel nanorods (503.42±210
nm) 107%;font-family:" times new roman>were prepared using the solvent diffusion method. Trastuzumab (TTZ) (Genentech)
was conjugated with the functionalized paclitaxel drug nanorods. The antibody
drug conjugate (PTXNR-TTZ) was further conjugated with the DOTA chelator for
radiolabeling with positron emitting 64Cu isotope. Cytotoxic T lymphocytes
were bound with PTXNR-TTZ in serum free un-supplemented RPMI 1640 medium. normal">

justify"> line-height:107%;font-family:" times new roman>

justify"> line-height:107%;font-family:" times new roman>

justify"> line-height:107%;font-family:" times new roman>Results

justify"> 107%;font-family:" times new roman>The SEM images confirm
the cylindrical or rod-like the shape of the paclitaxel drug particles in the
nano dimension of (503.42±210) 18.0pt;line-height:107%;font-family:" times new roman text1>× ( mso-bidi-font-size:11.0pt;line-height:107%;font-family:" times new roman mso-no-proof:yes>96.87±33)nm. The nanoparticle synthesis efficiency was 65%. Paclitaxel
nanorods were chemically activated using carbonyldiimidazole and conjugated to
monoclonal antibody trastuzumab with the conjugation efficiency of  53%. The drug NRs along with the antibody
conjugated PTXNR-TTZ showed enhanced stability in the biological media. PTXNR-TTZ
was bound on the surface of the cytotoxic T lymphocytes without inducing
apoptosis to the T cells. T-cell surface bound antibody conjugated drug
nanorods induced apoptosis in HER 2+ breast cancer cells resulting in significant
tumor clearence.