Abstract

Therapeutic drug monitoring (TDM) in cancer, while imperative, has been challenging due to inter-patient variability in drug pharmacokinetics. Additionally, most pharmacokinetic monitoring is done by assessments of the drugs in plasma, which is not an accurate gauge for drug concentrations in target tumor tissue. There exists a critical need for therapy monitoring tools that can provide real-time feedback on drug efficacy at target site to enable alteration in treatment regimens early during cancer therapy. Here, we report on theranostic optical imaging probes based on shortwave infrared (SWIR)-emitting rare earth-doped nanoparticles encapsulated with human serum albumin (abbreviated as ReANCs) that have demonstrated superior surveillance capability for detecting micro-lesions at depths of 1 cm in a mouse model of breast cancer metastasis. Most notably, ReANCs previously deployed for detection of multi-organ metastases resolved bone lesions earlier than contrast-enhanced magnetic resonance imaging (MRI). We engineered tumor-targeted ReANCs carrying a therapeutic payload as a potential theranostic for evaluating drug efficacy at the tumor site. In vitro results demonstrated efficacy of ReANCs carrying doxorubicin (Dox), providing sustained release of Dox while maintaining cytotoxic effects comparable to free Dox. Significantly, in a murine model of breast cancer lung metastasis, we demonstrated the ability for therapy monitoring based on measurements of SWIR fluorescence from tumor-targeted ReANCs. These findings correlated with a reduction in lung metastatic burden as quantified via MRI-based volumetric analysis over the course of four weeks. Future studies will address the potential of this novel class of theranostics as a preclinical pharmacological screening tool.

Highlights

  • Treatment of cancers through conventional chemotherapy or targeted therapy is challenging due to the heterogeneity of drug concentration in tumors as a result of varied tissue penetration and imperfect vasculature, which may lead to stasis of blood flow, large inter-capillary distances, and raised interstitial pressure (Tannock, 1998)

  • Prior studies established that cells respond to both rare earth albumin nanocomposites (ReANCs) and albumin nanocomposites without rare earth cores encapsulated within them (ANCs) (Naczynski et al, 2010)

  • Current clinical approaches for Therapeutic drug monitoring (TDM) in cancer involve assessing pharmacokinetic outputs, such as plasma drug concentration (Alnaim, 2007; Bartelink et al, 2019), and anti-tumor efficacy based on tumor regression and progression-free survival rates (McMahon and O’Connor, 2009)

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Summary

Introduction

Treatment of cancers through conventional chemotherapy or targeted therapy is challenging due to the heterogeneity of drug concentration in tumors as a result of varied tissue penetration and imperfect vasculature, which may lead to stasis of blood flow, large inter-capillary distances, and raised interstitial pressure (Tannock, 1998). Current therapeutic drug monitoring (TDM) tools offer a systemic outcome, such as a measure of a surrogate drug concentration in the plasma, which correlates with the overall outcome of tumor regression, but they fail to provide local drug concentrations at the lesion site. Resistance to chemotherapy regimens requires timely decisions for treatment alteration for improved disease outcomes (Kulkarni et al, 2016; Onafuye et al, 2019). The assessment of therapeutic outcomes requires a reliable TDM tool that can inform on drug pharmacokinetics at target site

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