Paclitaxel Delivery Systems: The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Carboxymethyldextran to Create Prodrugs

Abstract

Paclitaxel (Taxol ® ), an anti-microtubule agent isolated from the trunk bark of the Pacific Yew tree, Taxus brevifolia, 1) shows great promise as an anti-neoplastic agent for a variety of human cancers including breast, ovarian, non small cell lung, head and neck cancers, leukemia, and melanoma. [2][3][4][5][6] Its unique mechanism of action is related to its ability to promote microtubule assembly and inhibit cell replication in the late G2 or M phases of the cell cycle.7) A major problem associated with the administration of paclitaxel is its low solubility in water as well as in most pharmaceutically acceptable solvents. 21,22) and polymer-bound derivatives. 23,24) Although some of the dosage forms can be solubilized to release sufficient quantities of paclitaxel and have shown improved anti-tumor effects in animal models, problems-such as stability-have been observed.25) The use of macromolecules for the targeted delivery of anticancer agents has generated considerable interest regarding enhancing therapeutic efficacy and reducing systemic side effects, and some satisfactory results have been obtained. 26) We previously reported how to prepare carboxymethyldextran (CMDex) and doxorubicin (DXR) conjugates using a peptide linker, and in our evaluation we showed that CMDex with a suitable anionic nature and MW of more than 150 kDa increased retention of the conjugate in blood circulation and increased accumulation of DXR in tumors.27) Furthermore, CMDex-peptide-DXR conjugates containing a gly-gly-phegly spacer were more efficacious in a Walker-256 carcinoma rat model than a free DXR or a conjugate with no spacer. We chose CMDex as a candidate for a paclitaxel carrier since: CMDex is biocompatible; it contains a large number of carboxyl groups for the drug attachment and provides sufficient carrying capacity of the drug; and the resulting CMDex-drug conjugate has a high probability of being water-soluble.In this paper, we examine the synthesis and evaluation of CMDex-paclitaxel conjugates bound with an ester bond and using amino acid linkers, namely, gly, ala, leu, and ile. We also look at how polymeric modification of paclitaxel with CMDex significantly improves water solubility and antitumor activity. The gly linker was introduced into the 2Ј-hydroxyl group to form CMDex-2Ј-gly-paclitaxel and into the 7-hydroxyl group to form CMDex-7-gly-paclitaxel. All other amino acid linkers-ala, leu, and ile-were introduced only into the 2Ј-hydroxyl group of paclitaxel. These were all designed to be water-soluble. The amounts of paclitaxel released from the conjugates during incubation with a buffer and mouse plasma at 37°C were measured by HPLC. We compared this to their in vivo tumor distribution and in vivo anti-tumor effects in a paclitaxel resistant tumor mouse model (colon 26). The tumor and body weights of the mice were monitored after continuous intravenous administration. Paclitaxel was bound via its hydroxyl group to carboxymethyldextran (CMDex, 150 kDa) by means of an amino acid linker; the linker was intr...

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

“…These experiments clearly demonstrate the higher stability of carbamate linkage over the ester bond (compounds 3 and 4) and also indicate that the modification of the more hindered C7 position lead to reduction of hydrolysis rate of the conjugates as also reported by other authors (Greenwald et al,350 1995; Sugahara et al, 2002). The stability was further improved with the introduction of PEG at both C2' and C7 positions.…”

Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo

“…The amino acid linkages are relatively weak bonds; under certain conditions, the chemical bonds could break and release the drugs easily. 56 PEG as linker for the production of prodrugs has been widely investigated. 57,58 However, in vivo experiments have shown that a PEG drug system has lower efficacy than the drug alone.…”

Carrier Effects on Antitumor Activity and Neurotoxicity of AZ10992, a Paclitaxel-Carboxymethyl Dextran Conjugate, in a Mouse Model

“…9) We previously reported the necessity of controlled paclitaxel release to achieve antitumor effects in a colon26 carcinomabearing mouse model. 29) In that report, we discussed that the appropriate drug release rates from conjugates are essential to achieve antitumor effects. AZ10992 would be predicted to have more controlled drug release via the peptide linker as compared with the other paclitaxel dosage forms.…”