Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy

Abstract

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7–28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

“… 3,5 It has been reported that nanoparticles are internalised into intracellular compartments (endosomes or lysosomes) with high heterogeneity within and between different tumour types and cancer cell types. 36 In particular, the accumulation of binary ratiometric reporter nanospheres in six animal tumour models including breast and pancreatic tumour types, and the endocytosis kinetics of these nanoparticles in the breast and pancreatic cancer cells were highly heterogeneous. 36 Furthermore, differences in the endosomal compartments between cell types exist which may also result in differences in the protein corona formed around the nanoparticles.…”

“… 36 In particular, the accumulation of binary ratiometric reporter nanospheres in six animal tumour models including breast and pancreatic tumour types, and the endocytosis kinetics of these nanoparticles in the breast and pancreatic cancer cells were highly heterogeneous. 36 Furthermore, differences in the endosomal compartments between cell types exist which may also result in differences in the protein corona formed around the nanoparticles. Again this may change the endosomal escape properties of nanoparticles.…”

How can we use the endocytosis pathways to design nanoparticle drug-delivery vehicles to target cancer cells over healthy cells?

“…10). 174,175 The pH of endosomes and lysosomes of cancer cells is often lower than in healthy cells, which can be used to trigger the drug release in cancer cells. [176][177][178] Qiu et al used mixed-charged gold nanoparticles to accumulate in lysosomes, disrupt the lysosomal membrane, and kill cancer cells without the use of any anticancer drugs.…”

“…It was recently found that the accumulation of B25 nm binary ratiometric reporter nanospheres (two-modular nano-reporter system with a transition in florescence emission according to pH of the intracellular and extracellular environments) into six animal tumor models including breast and pancreatic cancer tumor types, and the endocytosis kinetics of these nanoparticles into the breast and pancreatic cancer cells (MCF7 and PANC-2) were highly heterogeneous. 185 In addition, endosomal and lysosomal escape kinetics of nanoparticles have cell line-specific differences. 186,187 These differences might arise because the endosomal compartments are different between cell types or it might be because of other differences in the protein corona formed that may change nanoparticle fusion and endosomal escape properties.…”

Localization and Absolute Quantification of Dopamine in Discrete Intravesicular Compartments Using NanoSIMS Imaging

“…Intracellular drug distribution is also an important parameter, and drug delivery targeting specific intracellular compartments can help to achieve better bioavailability and activity of drugs, as well as improved delivery systems [ 3 , 4 , 5 ]. Thus, development and improvement of analytical methods for both high resolution localization and absolute quantification of chemicals intracellularly are essential [ 6 , 7 , 8 ].…”