Targeted in vivo imaging of tumour and stromal cells within a complex tumour microenvironment

IntroductionThere is growing awareness of the importance of the tumour microenvironment (TME) in determining how cancer patients respond to therapy. To optimally screen drugs during pre-clinical drug development in animal... [ view full abstract ]

Introduction

There is growing awareness of the importance of the tumour microenvironment (TME) in determining how cancer patients respond to therapy. To optimally screen drugs during pre-clinical drug development in animal models, translate them into the clinic, and determine optimal timing of drug combinations, imaging systems that can monitor individual components of the TME and their response to therapy are required. Recently, quantum dots (QDs)^1,2 have emerged as bioimaging probes and near-infrared (NIR) QDs, emitting in the ‘biological window’ of wavelengths where tissue and water absorbance is minimal and penetration of light into tissue is maximal, offer numerous advantages compared to conventional fluorophores.

Methods

We have developed PbS QDs emitting in the NIR region and have tailored their surface chemistry to allow for bioconjugation of bioorganic molecules. Contemporaneously, targeting peptides, selected from the current literature, have been tested in complex tumour microenvironments such as 3D spheroids of both colorectal cancer cells with fibroblasts, and a co-culture of cancer cells, fibroblasts and endothelial cells.

Results

We have developed protocols for the optimal synthesis of NIR QDs and studied their in vivo biodistribution (Figure 1). We have also identified peptides that specifically target individual cells in the TME (Figure 2 and Figure 3). Our QDs can be targeted to individual elements of the tumour microenvironment after establishing protocols for the bioconjugation of targeting peptides on their surfaces.

Discussion

We have demonstrated the in vivo biocompatibility of the PbS NIR QDs for the first time. We have also shown that the peptide-mediated targeting is effective in complex 3D in vitro models in which cancer cells, fibroblasts and endothelial cells are grown in co-culture, and spheroid models which better represent the complexity of patient tumours and xenografts than standard 2D cancer models. 

In the end, QDs carrying these targeting peptides have potential in vivo to allow real-time monitoring of the presence of cancer and stromal components during xenograft establishment.

References:

(1) Jing, L.; Kershaw, S. V.; Li, Y.; Huang, X.; Li, Y.; Rogach, A. L.; Gao, M. Chem. Rev. 2016, 116, 10623.

(2) Smith, B. R.; Gambhir, S. S. Chem. Rev. 2017, 117, 901.