Synthesis and Evaluation of Water-Soluble Poly(vinyl alcohol)-paclitaxel Conjugate as a Macromolecular Prodrug

Abstract

Paclitaxel (PTX) is an anti-microtubule agent isolated from the trunk bark of the Pacific Yew tree, Taxus brevifolia.1) It has been widely used as an anti-neoplastic agent for a variety of human cancers including breast, ovarian, nonsmall cell lung, head and neck cancers, leukemia, and melanoma. [2][3][4][5][6] PTX is a highly hydrophobic drug and is hardly soluble in water (water solubility Ͻ0.3 mg/ml).7) Because of its poor solubility in water and many other acceptable pharmaceutical solvents, specific emulsionizers, such as Cremophor EL ® , are used to formulate PTX in commercial injection solutions. However, serious hypersensitivity reactions have been reported in some individuals since the content of Cremophor EL ® used in the PTX formulation is significantly higher than in any other marketed drug. 8,9) Side effects of PTX formulation include nausea and vomiting, diarrhea, mucositis, myelosuppression, cardiotoxicity and neurotoxicity. 10,11) In addition, Cremophor EL ® is known to leach phthalate plasticizers from polyvinylchloride bags and intravenous tubing.12) Therefore, alternative dosage forms for the PTX administration need to be developed to reduce the undesirable side effects induced by using Cremophor EL ® . In recent years the use of water-soluble polymers as drug delivery systems has been received increasing attention. Li et al. 13) and Greenwald et al. 14) reported the conjugation of polyethylene glycol (PEG) to the 2Ј-position of PTX through a spacer succinyl group. They demonstrated that PEG may be used as an effective solubilizing carrier for PTX. Poly-Lglutamic acid was also used to make a water-soluble PTX conjugate. [15][16][17] It was demonstrated that the poly-(L-glutamic acid)-paclitaxel conjugate was more effective than standard PTX. On the other hand, Sugahara et al. constructed the PTX delivery system using amino acid linkers in the conjugation of PTX with carboxymethyldextran. 18)The consequence of attachment of low molecular weight drugs to macromolecular carriers alters their rate of excretion from the body, changes their toxicity and immunogenicity, and limits their uptake by cells via endocytosis, thus providing the opportunity to direct the drug to the particular cell type where its activity is needed. 19) In addition, these macromolecular conjugates can accumulate in solid tumors due to the enhanced microvasculature of tumor tissue. 20,21) This phenomenon has been termed enhanced permeability and retention in relation to tumor targeting (EPR-phenomenon). [22][23][24] Poly(vinyl alcohol) (PVA) is a polymer which is synthesized by polymerizing not a vinyl alcohol monomer but a vinyl acetate monomer. This monomer is polymerized in to poly(vinyl acetate) and then hydrolyzed to produce PVA. PVA's biocompatibility makes it an excellent material for use in medical applications such as soft contact lenses. Recently, PVA has been used for long-term implants, including a bioartificial pancreas, artificial cartilage, nonadhesive film, and esophagus or scleral buckling material. 25) Fur...

Somatostatin Receptor–Mediated Specific Delivery of Paclitaxel Prodrugs for Efficient Cancer Therapy

“…Solubilities of OCT(Phe)–PEG–PTX and mPEG–PTX prodrugs were evaluated using a visual observation method …”

Poly(Vinyl Alcohol) Physical Hydrogels: New Vista on a Long Serving Biomaterial

“…In vivo and in vitro studies demonstrated that conjugation with the hydrophilic polymer significantly increased water solubility of the drug and enhanced its antitumor effect against neuroblastoma cells. Other examples of CDI‐mediated coupling with PVA include immobilization of lipase onto a hybrid polysiloxane‐PVA matrix,66 a strategy which delivered a total of 95% recovery of the enzyme hydrolytic activity and an increased thermal stability of the protein, and a multi‐step synthetic pathway yielding a PVA‐paclitaxel bioconjugate with utility in anticancer therapy 67. Activation of PVA hydroxyl groups can also be performed using 4‐nitrophenylchloroformate (NPC), as reported by Arranz and coworkers68 as an approach for conjugation with 2‐amino‐2‐deoxy‐ D ‐glucose (glucosamine).…”

Recent Progress in the Chemistry and Biology of Paclitaxel (TaxolTM) and Related Taxanes

“…can increase the water solubility and enhance the bioavailability of prodrugs. For example, in prodrug 4.1.19, paclitaxel is conjugated with a highly hydrophilic polyethylene glycol (PEG) polymer [229], and in 4.1.20 (Figure 8.50) it is conjugated with poly(vinyl alcohol) (PVA) units [230]. In both cases, the water solubility was greatly enhanced and both prodrugs allowed fast release of the parent.…”