Synthesis and Biological Evaluation (in Vitro and in Vivo) of Cyclic Arginine–Glycine–Aspartate (RGD) Peptidomimetic–Paclitaxel Conjugates Targeting Integrin α_Vβ₃

Abstract

A small library of integrin ligand-paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified αVβ3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin αVβ3, making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.

The Effects of Solvent and Added Bases on the Protection of Benzylamines with Carbon Dioxide

“…The model compound, (4-(aminomethyl)phenyl)methanol (14) was prepared from 4-aminomethylbenzoic acid by reduction with LiAlH4 following as described in literature [20]. Briefly, 4-aminomethylbenzoic acid (2.0 g; 1 eq) was added to a round bottom flask equipped with a stir bar and condenser.…”

“…Only the alcohol reacted with 15% and 30% yield of the O-acylated product after 6 h. It is noted that the O-acylation appeared to proceed slower with the carbamate species than with its free amine analog. However, in presence of 1% triazole catalyst over a period of 24 h, 80% of the O-acylated product (20) and (21) …”

Design and Synthesis of an RGD Peptidomimetic-Paclitaxel Conjugate Targeting αvβ3 Integrin for Tumour-Directed Drug Delivery

“…Several studies in this field provided experimental evidence that RGDbased strategies contribute to reduce the toxicity and augment the therapeutic window of existing chemotherapeutics. 1,4,5 …”

“…Usually, amides, hydrazides, carbamates and sterically hindered esters are used to connect the cytotoxic drug to the tumour-homing moiety through a linker. 4,7 Conjugation of PTX to RGD ligands could be performed via cleavable succinyl ester linker attached to the 2′-OH group of PTX (Scheme 1). As the 2′-OH function is essential for PTX to exert its cytotoxic and microtubule-stabilising activities, it should be easily released from the ester function once delivered to the target organ.…”

“…8 It has been shown that the succinyl ester bond at the PTX-2′ position is sufficiently stable to guarantee tumour-selective delivery of RGD-PTX conjugates and is enzymatically cleaved in vivo by esterases to provide PTX into its active form. 4 While the cytotoxic agent is converted into an inactive prodrug by coupling to an RGD carrier, the RGD-ligand should maintain its capacity to bind the αvβ3 receptor when attached to the cytotoxic payload. In this regard, SAR studies conducted on triazole-based RGD mimetics 6 provided essential information for the rational design of active derivatives functionalised with a handle necessary for the ligation of the cytotoxic cargo.…”