Boronated Dendrimers Delivered by Receptor Ligands 6531 Epidermal Growth Factors EGF

Due to its increased expression in a variety of tumors, including high-grade gliomas, and its low or undetectable expression in normal brain, EGFR is an attractive target for cancer therapy.68-70 As described above, targeting of EGFR has been carried out using either mAbs or alternatively, as described in this section, EGF, which is a single-chain, 53-mer heat and acid stable polypeptide.

HO O

O OH

Cetuximab (C225)

NalO4

O OH

C225-CHO

5th generation PAMAM dendrimer o

SPDP-G5

Na(CH3)3NB10H8NCO

SPDP-G5-B1100 DTT

KMUH-G5-B1

SO N

C225-G5-B1

HS-G5-B1

KMUH-G5-B1

FIGURE 6.3 Conjugation scheme for linkage of a boron-containing dendrimer to the monoclonal antibody, C225 (cetuximab), which is directed against EGFR. (From Wu, G. et al., Bioconjug. Chem., 15, 185, 2004; Barth, R. F. et al., Appl. Radiat. Isot. 61, 899, 2004. With permission.)

It binds to a transmembrane glycoprotein with tyrosine kinase activity, which triggers dimerization and internalization.71,72 Because the EGF boron bioconjugates have a much smaller MW than mAb conjugates, they should be capable of more rapid and effective tumor targeting than has been observed with mAbs.67,73

The procedure used to conjugate EGF to a boronated dendrimer was slightly different from that used to boronate mAbs. A fourth-generation PAMAM dendrimer was reacted with the isocyanato polyhedral borane Na(CH3)3NB10H8NCO. Next, reactive thiol groups were introduced into the boronated dendrimer using SPDP, and EGF was derivatized with sulfo-MBS. The reaction of thiol groups of the derivatized, boronated starburst dendrimer (BSD) with maleimide groups produced a stable BSD-EGF bioconjugate, which contained approximately 960 atoms of boron per molecule of EGF.74 The BSD-EGF initially was bound to the cell surface membrane and then was endocytosed, which resulted in accumulation of boron in lysosomes.74 Subsequently, in vitro and in vivo studies were carried out to evaluate the potential efficacy of the bioconjugate as a boron delivery agent for BNCT.73 As will be described in more detail later on in this review, therapy studies demonstrated that F98EGFR-glioma-bearing rats that received either boronated EGF or mAb by either direct i.t. injection or convection enhanced delivery into the brain had a longer mean survival time (MST) than animals bearing F98 parental tumors following BNCT.75-77

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