Semiconducting polymer nanoparticles for photothermal ablation of colorectal cancer organoids

Bryce Mccarthy,Shay Soker,Amit Cudykier,Ravi Singh,Nicole Levi-Polyachenko

doi:10.1038/s41598-021-81122-w

Abstract

Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant. Targeted theranostic nanoparticles (NPs) that can produce heat for ablation and enable tumor visualization via their fluorescence offer advantages for detection and treatment of disseminated small nodules. A major hurdle in clinical translation of nanoparticles is their interaction with the 3D tumor microenvironment. To address this problem tumor organoid technology was used to evaluate the ablative potential of CD44-targeted polymer nanoparticles using hyaluronic acid (HA) as the targeting agent and coating it onto hybrid donor acceptor polymer particles (HDAPPs) to form HA-HDAPPs. Additionally, nanoparticles composed from only the photothermal polymer, poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b’]dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe), were also coated with HA, to form HA-BSe NPs, and evaluated in 3D. Monitoring of nanoparticle transport in 3D organoids revealed uniform diffusion of non-targeted HDAPPs in comparison to attenuated diffusion of HA-HDAPPs due to nanoparticle-matrix interactions. Computational diffusion profiles suggested that HA-HDAPPs transport may not be accounted for by diffusion alone, which is indicative of nanoparticle/cell matrix interactions. Photothermal activation revealed that only HA-BSe NPs were able to significantly reduce tumor cell viability in the organoids. Despite limited transport of the CD44-targeted theranostic nanoparticles, their targeted retention provides increased heat for enhanced photothermal ablation in 3D, which is beneficial for assessing nanoparticle therapies prior to in vivo testing.

Highlights

Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant
Hydrodynamic diameter as measured by dynamic light scattering (DLS) indicates an initial measurement of 133.6 nm (± 1.3 nm) prior to coating, which displays a stepwise increase to 149.0 nm (± 1.6 nm) when coated with chitosan and to 189.1 nm (± 1.3 nm) with the addition of hyaluronic acid (HA) (Supplementary Figure S1)
Fluorescence measurement with nanoparticle tracking analysis (NTA) allows for detection of potentially non-encapsulated fluorophores that would be indicated by a small measured particle size

Summary

Introduction

Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant. A major hurdle in clinical translation of nanoparticles is their interaction with the 3D tumor microenvironment To address this problem tumor organoid technology was used to evaluate the ablative potential of CD44-targeted polymer nanoparticles using hyaluronic acid (HA) as the targeting agent and coating it onto hybrid donor acceptor polymer particles (HDAPPs) to form HA-HDAPPs. nanoparticles composed from only the photothermal polymer, poly[4,4-bis(2-ethylhexyl)cyclopenta[2,1-b;3,4-b’]dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe), were coated with HA, to form HA-BSe NPs, and evaluated in 3D. Termed Hybrid Donor–Acceptor Polymer Particles (HDAPPs), our group has demonstrated the capacity of HDAPPs to reproducibly heat by photoexcitation within the NIR window, generate fluorescence emission with minimal photobleaching within the NIR window (825 nm), remain colloidally stable to indefinite time points, and show minimal cytotoxicity, even up to 1 mg/ ml[22,23,24] The combination of these characteristics into a single targetable nanoparticle platform demonstrates the utility of HDAPPs as a photothermal theranostic for both detection and ablation of CRC. Anisotropic diffusion of nanoparticles within the tumor microenvironment may be a major barrier to therapeutic success, and it is this limitation that the current work has sought to illucidate[26]

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