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Chlorin e6-Conjugated and PEGylated Immune Checkpoint Inhibitor Nanocomposites for Pulmonary Metastatic Colorectal Cancer.

ABSTRACT: Here we demonstrate theranostic immune checkpoint inhibitor nanocomposites (ICI NC) having an improved tumor targeting ability in pulmonary metastatic colon cancer model. Atezolizumab, a PD-L1 antibody, was conjugated with methoxy poly(ethylene glycol) (MePEG) and chlorin e6 (Ce6) via cathepsin-B-sensitive peptide as a linkage (named as ICI nanocomposites, ICI NC). This ICI NC is delivered to tumor sites enriched with tumor-specific enzymes such as cathepsin B, whereas undesired ICI exposure to normal tissue is avoided. When ICI NC were incubated with cathepsin B, Ce6 was released from ICI NC with increased fluorescence intensity in cathepsin B dose-dependent manner, which was by degradation of the peptide and then liberated Ce6 was activated in the aqueous solution. In animal pulmonary metastasis model using CT26 cells, ICI NC showed superior tumor targetability, i.e., fluorescence intensity was significantly strong in the mouse lung having metastatic tumor. On the contrary, cathepsin-B-deficient carriers such as atezolizumab-Ce6 conjugates or atezolizumab-Ce6/MePEG conjugates showed strong fluorescence intensity in the liver as well as lung. Our proposed ICI NC may be used for theranostic cancer therapy with superior tumor specificity of releasing ICI and Ce6 into tumor microenvironment, thereby showing an efficient inhibitory effect on pulmonary metastasis of CT26 cells.

SUBMITTER: Jeong YI

PROVIDER: S-EPMC6854570 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Chlorin e6-Conjugated and PEGylated Immune Checkpoint Inhibitor Nanocomposites for Pulmonary Metastatic Colorectal Cancer.

Jeong Young-Il YI Yoo So Young SY Heo Jeong J Kang Dae Hwan DH

ACS omega 20191101 20

Here we demonstrate theranostic immune checkpoint inhibitor nanocomposites (ICI NC) having an improved tumor targeting ability in pulmonary metastatic colon cancer model. Atezolizumab, a PD-L1 antibody, was conjugated with methoxy poly(ethylene glycol) (MePEG) and chlorin e6 (Ce6) via cathepsin-B-sensitive peptide as a linkage (named as ICI nanocomposites, ICI NC). This ICI NC is delivered to tumor sites enriched with tumor-specific enzymes such as cathepsin B, whereas undesired ICI exposure to ...[more]

PMID: 31737818

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Project description:The main purpose of this study is to synthesize novel types of nanophotosensitizers that are based on hyperbranched chlorin e6 (Ce6) via disulfide linkages. Moreover, hyperbranched Ce6 was conjugated with hyaluronic acid (HA) for CD44-receptor mediated delivery and redox-sensitive photodynamic therapy (PDT) against cancer cells. Hyperbranched Ce6 was considered to make novel types of macromolecular photosensitizer since most of the previous studies regarding nanophotosensizers are concerned with simple conjugation between monomeric units of photosensitizer and polymer materials. Hyperbranched Ce6 was synthesized by conjugation of Ce6 each other while using disulfide linkage. To synthesize Ce6 tetramer, carboxyl groups of Ce6 were conjugated with cystamine and three equivalents of Ce6 were then conjugated again with the end of amine groups of Ce6-cystamine. To synthesize Ce6 decamer as a hyperbranched Ce6, six equivalents of Ce6 was conjugated with the end of Ce6 tetramer via cystamine linkage. Furthermore, HA-cystamine was attached with Ce6 tetramer or Ce6 decamer to synthesize HA-Ce6 tetramer (Ce6tetraHA) or HA-Ce6 decamer (Ce6decaHA) conjugates. Ce6tetraHA and Ce6decaHA nanophotosensitizers showed small diameters of less than 200 nm. The addition of dithiothreitol (DTT) and hyaluronidase (HAse) induced a faster Ce6 release rate in vitro drug release study, which indicated that Ce6tetraHA nanophotosensitizers possess redox-sensitive and HAse-sensitive release properties. Ce6tetraHA nanophotosensitizers showed higher intracellular Ce6 accumulation, higher ROS generation, and higher PDT efficacy than that of Ce6 alone. Ce6tetraHA nanophotosensitizers responded to the CD44 receptor of cancer cell surface, i.e., the pre-treatment of HA blocked CD44 receptor of U87MG or HCT116 cells and then inhibited delivery of nanophotosensitizers in vitro cell culture study. Furthermore, in vivo tumorxenograft study showed that fluorescence intensity in the tumor tissues was stronger than those of other organs, while CD44 receptor blocking by HA pretreatment induced a decrease of fluorescence intensity in tumor tissues when compared to liver. These results indicated that Ce6tetraHA nanophotosensitizers delivered to tumors by redox-sensitive and CD44-sensitive manner.

Dataset Information

Chlorin e6-Conjugated and PEGylated Immune Checkpoint Inhibitor Nanocomposites for Pulmonary Metastatic Colorectal Cancer.

Publications

Chlorin e6-Conjugated and PEGylated Immune Checkpoint Inhibitor Nanocomposites for Pulmonary Metastatic Colorectal Cancer.

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