Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors

TY - JOUR

T1 - Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors

AU - Bofinger, Robin

AU - Weitsman, Gregory

AU - Evans, Rachel

AU - Glaser, Matthias

AU - Sander, Kerstin

AU - Allan, Helen

AU - Hochhauser, Daniel

AU - Kalber, Tammy L

AU - Årstad, Erik

AU - Hailes, Helen C

AU - Ng, Tony

AU - Tabor, Alethea B

N1 - Funding Information: Robin Bofinger, Gregory Weitsman, Rachel Evans, Matthias Glaser, Kerstin Sander and Tammy Kalber performed the experiments (chemical and peptide synthesis, cancer cell biology, FRET/FLIM, radiochemistry and biodistribution). Helen Allan, Robin Bofinger, Gregory Weitsman and Alethea Tabor wrote the initial draft, and all authors contributed to writing and reviewing the final draft. Erik Arstad, Daniel Hochhauser, Tammy Kalber, Helen Hailes, Tony Ng and Alethea Tabor supervised the research groups, and Tammy Kalber, Erik Arstad, Tony Ng and Alethea Tabor acquired the financial support for the research. Funding Information: This work was conducted within the King’s College London-UCL Comprehensive Cancer Imaging Centre (CCIC) supported by Cancer Research UK and the EPSRC, in association with MRC and DoH (UK). The authors would like to thank Cancer Research UK and the EPSRC (C5255/A15935 (RB, GW, MG, KS)) for financial support. We also thank the EPSRC for the award of an Early Career Fellowship EP/L006472/1 (TK). The radiochemistry work (MG, KS, EA) was undertaken at the UCL Centre for Radiopharmaceutical Chemistry, which is funded in part by the Department of Health’s NIHR Biomedical Research Centres funding scheme. We thank Dr Kersti Karu and Dr Abil Aliev for assistance with mass spectrometry and NMR, and also acknowledge Dr Stephen McCarthy and Aamina Murtza for additional HPLC and NMR characterization. Publisher Copyright: © 2021 The Royal Society of Chemistry.

PY - 2021/11/28

Y1 - 2021/11/28

N2 - In vivo delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes. These simultaneously deliver an inhibitor of the EGFR tyrosine kinase, and plasmid DNA coding for a Crk-based biosensor, Picchu-X, which when expressed in the target cells can be used to quantify the inhibition of EGFR in vivo in a mouse colorectal cancer xenograft model. Reversible bioconjugation of a known analogue of the tyrosine kinase inhibitor Mo-IPQA to a cationic peptide, and co-formulation with peptides containing both EGFR-binding and cationic sequences, allowed for good levels of inhibitor encapsulation with targeted delivery to LIM1215 colon cancer cells. Furthermore, high levels of expression of the Picchu-X biosensor in the LIM1215 cells in vivo allowed us to demonstrate, using fluorescence lifetime microscopy (FLIM)-based biosensing, that EGFR activity can be successfully suppressed by the tyrosine kinase inhibitor, released from the lipopolyplexes. Finally, we measured the biodistribution of lipopolyplexes containing 125I-labelled inhibitors and were able to demonstrate that the lipopolyplexes gave significantly higher drug delivery to the tumors compared with free drug.

AB - In vivo delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes. These simultaneously deliver an inhibitor of the EGFR tyrosine kinase, and plasmid DNA coding for a Crk-based biosensor, Picchu-X, which when expressed in the target cells can be used to quantify the inhibition of EGFR in vivo in a mouse colorectal cancer xenograft model. Reversible bioconjugation of a known analogue of the tyrosine kinase inhibitor Mo-IPQA to a cationic peptide, and co-formulation with peptides containing both EGFR-binding and cationic sequences, allowed for good levels of inhibitor encapsulation with targeted delivery to LIM1215 colon cancer cells. Furthermore, high levels of expression of the Picchu-X biosensor in the LIM1215 cells in vivo allowed us to demonstrate, using fluorescence lifetime microscopy (FLIM)-based biosensing, that EGFR activity can be successfully suppressed by the tyrosine kinase inhibitor, released from the lipopolyplexes. Finally, we measured the biodistribution of lipopolyplexes containing 125I-labelled inhibitors and were able to demonstrate that the lipopolyplexes gave significantly higher drug delivery to the tumors compared with free drug.

UR - http://www.scopus.com/inward/record.url?scp=85119720324&partnerID=8YFLogxK

U2 - 10.1039/d1nr02770k

DO - 10.1039/d1nr02770k

M3 - Article

C2 - 34730152

SN - 2040-3364

VL - 13

SP - 18520

EP - 18535

JO - Nanoscale

JF - Nanoscale

IS - 44

ER -