TMZ-BioShuttle – a reformulated Temozolomide

Abstract

There is a large number of effective cytotoxic drugs whose side effect profile, efficacy, and long-term use in man are well understood and documented over decades of use in clinical routine e.g. in the treatment of recurrent glioblastoma multiforme (GBM) and the hormone-refractory prostate cancer (HRPC). Both cancers are insensitive against most chemotherapeutic interventions; they have low response rates and poor prognoses. Some cytotoxic agents can be significantly improved by using modern technology of drug delivery or formulation. We succeeded to enhance the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic temozolomide (TMZ) as an example. The TMZ connection to transporter molecules (TMZ-BioShuttle) resulted in a much higher pharmacological effect in glioma cell lines while using reduced doses. This permits the conclusion that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The re-formulation of TMZ to TMZ-BioShuttle achieved a nearly 10-fold potential of the established pharmaceutic TMZ far beyond the treatment of brain tumors cells and results in an attractive reformulated drug with enhanced therapeutic index.

A Peptide & Peptide Nucleic Acid Synthesis Technology for Transporter Molecules and Theranostics - The SPPS

“…The TMZ-BioShuttle resulted in a higher pharmacological effect in glioblastoma cell lines dramatically with reduced doses. This permits the conclusion that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation as first described by Waldeck in 2008 66. The synthesis steps were published by Pipkorn in 2009.…”

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“…It was exemplarily documented in the field of drug-re-formulation, which dramatically increased the therapeutic potential of classic drugs as pointed out here with the alkylating agent temozolomide (TMZ). It was also able to enhance the therapeutic spectrum in malignant gliomas or in hormone-refractory prostate cancer 65,66,164 . Additionally this DAR inv technology attracts increasing notice to further medical applications, especially in oncological diagnostics and therapy at the cellular and molecular level.…”

“…The functionalization of a diaryl-tetrazine with "old fashioned" drugs like temozolomide (TMZ) and the effects of the DAR inv . reaction product were first documented by the Wiessler group as an important example of reformulation of established drugs 65 .…”

“…The syntheses of the Reppe-Anhydride 44 and the corresponding () Boc-Lys derivative 46 were described 65 .…”

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

“…A conjugation of temozolomide has been accomplished by using cycloaddition reactions, in which the dien-component is obtained by coupling the amide group of the temozolomide with a tetrazine. TMZ-BioShuttle, formed by covalent chemical conjugation of temozolomide to a transmembrane transport peptide, has been reported to have better in vitro activity against some glioma cell lines at reduced dose levels, suggesting its potential to minimize systemic side effects [109]. The TMZ-BioShuttle may be able to take advantage of the AMT and the RMT [110].…”