In situ dose amplification by apoptosis-targeted drug delivery

doi:10.1016/j.jconrel.2011.06.043

Journal of Controlled Release

Volume 154, Issue 3, 25 September 2011, Pages 214-217

https://doi.org/10.1016/j.jconrel.2011.06.043 Get rights and content

Abstract

When tumor cells undergo apoptosis in response to chemotherapy, the levels of apoptotic biomarkers such as histone H1 are increased at the tumor. This would amplify in situ homing signals and thus drug delivery by apoptosis-targeted drugs. To examine this possibility, we prepared apoptosis-targeted liposomes containing doxorubicin by labeling them with the CQRPPR peptide (ApoPep-1) that recognizes apoptotic cells by binding to histone H1. ApoPep-1-labeled liposomes, but not folate-labeled liposomes, inhibited tumor growth in mice more efficiently than untargeted liposomes, although in vitro cytotoxicities of those liposomes were similar. Fluorescence imaging signals at tumor were increased by the homing of ApoPep-1-labeled, fluorescent liposomes, which was correlated with the increase of apoptosis and the amount of doxorubicin at the tumor and, conversely, with the decrease of tumor volume. These results demonstrate that the apoptosis-targeted drug delivery enables in situ dose amplification and, when combined with imaging of apoptosis, provides a real-time monitoring of treatment response for cancer theragnosis.

Graphical abstract

Section snippets

Concept and hypothesis

Anti-cancer treatment based on targeted drug delivery is likely to enhance drug efficacy and reduce its side-effect. Conventional targeting strategies are directed against tumor-associated antigens, such as MUC-1 [1], or receptors that are over-expressed on tumor cell surface, such as transferrin receptor and folate receptor [2], [3]. Immunogenicity by tumor-associated antigens, however, seems to be relatively weak [1]. Moreover, the receptors over-expressed on tumor cells are ubiquitously

Experimental methods

Liposomes conjugated with polyethylene glycol (PEG) and loaded with doxorubicin (L-Dox), ApoPep-1-labeled L-Dox, folate-labeled L-Dox, and Cy7.5 near-infrared (NIR) fluorescence dye-labeled L-Dox were prepared as previously described [9]. The size of liposomes was 200 nm in diameter. Liposomes were PEGylated at 1.5 mol% of total lipids. ApoPep-1 or folate was conjugated to the end of PEG to minimize the interaction between the ligand and the surface of liposomes.

Cytotoxicity was determined by

Discovery and interpretation

For the apoptosis-targeted drug delivery, we labeled doxorubicin-loaded liposomes with ApoPep-1 and examined the cytotoxicity and anti-tumor growth activity of ApoPep-1-labeled liposomes as compared to untargeted and folate-labeled liposomes as controls. Folate binds to folate receptor that is over-expressed in many tumors and has been widely used as a tumor-targeting ligand [3]. All of the liposomes showed similar levels of in vitro cytotoxicity to H460 lung tumor cells (Fig. 1A). When

Conclusions

The main advantage of the apoptosis-targeted drug delivery over conventional strategies is the in situ dose amplification of homing signals (apoptotic biomarkers) and drug delivery in response to chemotherapy. The exposure of the homing signals on cell surface during apoptosis, not in normal condition, would be an additional advantage. Moreover, the combined imaging of apoptosis enables the real-time monitoring of treatment response and provides a novel strategy for cancer theragnosis.

Acknowledgments

This work was supported by the grant (F104AA010003-06A0101-00310), Basic Science Research Program (R11-2008-044-03002-0), and WCU Program (R33-10054) through the NRF of Korea funded by the Ministry of Education, Science and Technology.

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Concept paperIn situ dose amplification by apoptosis-targeted drug delivery

Abstract

Graphical abstract

Section snippets

Concept and hypothesis

Experimental methods

Discovery and interpretation

Conclusions

Acknowledgments

Int. J. Pharm.

Blood

J. Control. Release

J. Control. Release

J. Control. Release

Increased immunogenicity of tumor-associated antigen, mucin 1, engineered to express alpha-gal epitopes: a novel approach to immunotherapy in pancreatic cancer

Cancer Res.

Targeted drug delivery via folate receptors

Expert Opin. Drug Deliv.

Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages

J. Immunol.

Nucleosomes are exposed at the cell surface in apoptosis

J. Immunol.

Apoptotic release of histones from nucleosomes

J. Biol. Chem.

A novel peptide probe for imaging and targeted delivery of liposomal doxorubicin to lung tumor

Mol. Pharm.

Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors

PLoS One

Concept paper
In situ dose amplification by apoptosis-targeted drug delivery