Combination of Targeted Therapies for Colorectal Cancer Treatment.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (), and a β-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of and currently used to treat patients with this pathology.

A β-Cyclodextrin-Albumin Conjugate for Enhancing Therapeutic Efficacy of Cytotoxic Drugs.

Enhancing the selectivity of anticancer drugs currently used in the clinic is of great interest in order to propose more efficient chemotherapies with fewer side effects for patients. In this context, we developed a β-cyclodextrin trimer that binds to circulating albumin to form the corresponding bioconjugate in the bloodstream. This latter can then entrap doxorubicin following its i.

In vivo synthesis of triple-loaded albumin conjugate for efficient targeted cancer chemotherapy.

The development of selective anticancer drugs avoiding side effects met in the course of almost all current treatments is of major interest for cancer patients. Here, we report on a novel β-glucuronidase-responsive drug delivery system allowing the in vivo synthesis of triple-loaded albumin conjugate. Following intravenous administration, the glucuronide prodrug reacts in the blood stream with the cysteine-34 residue of circulating albumin through thio-Michael addition, enabling the bioconjugation of three Monomethylauristatin E (MMAE) molecules to the plasmatic protein.

Volatile Organic Compound Based Probe for Induced Volatolomics of Cancers.

The development of efficient protocols for cancer diagnosis remains highly challenging. An emerging approach relies on the detection in exhaled breath of volatile organic compounds (VOC) produced by tumours. In this context, described here is a novel strategy in which a VOC-based probe is converted selectively in malignant tissues, by a tumour-associated enzyme, for releasing the corresponding VOC.

Controlled Release of a Micelle Payload via Sequential Enzymatic and Bioorthogonal Reactions in Living Systems.

A bioorthogonal approach is explored to release the content of nanoparticles on demand. Exploiting our recently described click-and-release technology, we developed a new generation of cleavable micelles able to disassemble through a sequential enzymatic and bioorthogonal activation process. Proof-of-concept experiments showed that this new approach could be successfully used to deliver the substances encapsulated into micelles in living cells as well as in mice by two complementary targeted strategies.

A β-glucuronidase-responsive albumin-binding prodrug programmed for the double release of monomethyl auristatin E.

We report on the synthesis, and biological evaluations of a dimeric β-glucuronidase-responsive albumin-binding prodrug designed for the double release of MMAE upon a single enzymatic activation step. This prodrug produced a significant antitumour activity in mice bearing subcutaneous LS174T colorectal adenocarcinoma xenografts without inducing side effects.

A β-glucuronidase-responsive albumin-binding prodrug for potential selective kinase inhibitor-based cancer chemotherapy.

We report on the synthesis and in vitro biological evaluations of a nanomolar protein kinase inhibitor (PKI) and its β-glucuronidase-responsive albumin-binding prodrug. The highly potent PKI is 400-3400 times more cytotoxic than the well-known PKI Roscovitine. The prodrug is able to bind covalently to human serum albumin through Michael addition and release the cytotoxic PKI in the presence of β-glucuronidase, an enzyme over-expressed in the microenvironment of solid tumours.

Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid.

Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates.

Targeting the tumour microenvironment with an enzyme-responsive drug delivery system for the efficient therapy of breast and pancreatic cancers.

The development of novel therapeutic strategies allowing the destruction of tumour cells while sparing healthy tissues is one of the main challenges of cancer chemotherapy. Here, we report on the design and antitumour activity of a low-molecular-weight drug delivery system programmed for the selective release of the potent monomethylauristatin E in the tumour microenvironment of solid tumours. After intravenous administration, this compound binds covalently to plasmatic albumin through Michael addition, thereby enabling its passive accumulation in tumours where extracellular β-glucuronidase initiates the selective release of the drug.

Diminished oligomerization in the synthesis of new anti-angiogenic cyclic peptide using solution instead of solid-phase cyclization.

The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2.

A dendritic β-galactosidase-responsive folate-monomethylauristatin E conjugate.

We report the study of a new drug delivery system programmed for the selective internalisation and the subsequent enzyme-catalysed release of two monomethylauristatin E molecules inside FR-positive cancer cells. This targeting device is the most potent β-galactosidase-responsive folate-drug conjugate developed so far, killing cancer cells expressing a medium level of FR at low nanomolar concentrations.

A mechanically interlocked molecular system programmed for the delivery of an anticancer drug.

The development of mechanically interlocked molecular systems programmed to operate autonomously in biological environments is an emerging field of research with potential medicinal applications. Within this framework, functional rotaxane- and pseudorotaxane-based architectures are starting to attract interest for the delivery of anticancer drugs, with the ultimate goal to improve the efficiency of cancer chemotherapy. Here, we report an enzyme-sensitive [2]-rotaxane designed to release a potent anticancer drug within tumor cells.

An enzyme-responsive system programmed for the double release of bioactive molecules through an intracellular chemical amplification process.

The rise of chemical biology has led to the development of sophisticated molecular devices designed to explore and manipulate biological processes. Within this framework, we developed the first chemical system programmed for the selective internalization and subsequent enzyme-catalyzed double release of bioactive compounds inside a targeted population of cells. This system is composed of five distinct units including a targeting ligand, an enzymatic trigger, a self-immolative linker and two active compounds articulated around a chemical amplifier.

A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts.

Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR).