In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery
Introduction
Paclitaxel has demonstrated significant activity in clinical trials against a wide variety of tumors, especially, ovarian and breast cancer in the past 10–20 years. However, due to its high hydrophobicity, an adjuvant such as Cremophor EL has to be used to prepare injection as its clinical dosage form. Unfortunately, Cremophor EL causes serious side-effects and leads to hypersensitivity reactions in many patients (Panchagnula, 1998, Dhanikula and Panchagnula, 1999, Singla et al., 2002). In order to increase therapeutic efficiency and reduce side-effects, much effort has been devoted to the development of tumor-targetable DDS of paclitaxel such as liposomes (Sampedro et al., 1993, Sharma and Straubinger, 1994, Crosasso et al., 2000), nanoparticles (Suh et al., 1998, Fonseca et al., 2002, Mu and Feng, 2002, Mu and Feng, 2003, Kim et al., 2003, Mitra and Lin, 2003, Potineni et al., 2003), parenteral emulsion (Lundberg, 1997, Kan et al., 1999), water-soluble prodrugs and conjugates (Rodrigues et al., 1995, Dosio et al., 1997, Pendri et al., 1998, Safavy et al., 2003). So far, the different approaches investigated have shown a lot of promise to replace the Cremophor EL-based vehicle for paclitaxel delivery, but except liposomes, the final product for human use is still far away.
In general, solid tumors show hypervascular permeability and impaired lymphatic drainage. Due to such effects, macromolecules or nanoparticles (<200 nm) can significantly accumulate in tumor, however, this behavior belongs to passive mechanism and lacks go-aheadism to recognize and bind to tumor cell or tissue. It has been reported that the membrane transferrin receptor-mediated endocytosis of the complex of transferrin bound iron and transferrin receptor is the major route of cellular iron uptake, and the efficient cellular uptake pathway has been exploited for the site-specific delivery of anti-tumor drugs, protein and therapeutic gene into proliferating cells including erythroblasts and cancer cells that overexpress transferrin receptor (Wagner et al., 1994, Li and Qian, 2002). The conjugation of transferrin with drugs is usually performed either directly by chemical conjugation or genetically by infusion of peptides/proteins into the structure of transferrin. Although direct coupling methods are easy to carry out, they show some disadvantages, such as polymeric products are likely to be formed during the preparation, and the resulting conjugates are chemically poorly defined with respect to the chemical link between drugs and carrier proteins (Kratz and Beyer, 1998, Singh, 1999). In addition, it has shown that transferrin-coupled liposomes significantly enhanced uptake of free doxorubicin or α-IFN via the receptor-mediated mechanism (Liao et al., 1998, Eavarone et al., 2000). So, the design of PEG-coated biodegradable polycyanoacrylate nanoparticles conjugated to transferrin (transferrin-PEG nanoparticles), an actively targetable nanoparticles (ATN) as paclitaxel carriers could be one of the ideal solutions to deliver paclitaxel to tumor because ATN has double effect from passive and active mechanism.
Previously, we prepared nanoparticles bearing polyethylene glycol-coupled transferrin for delivery of pDNA, and the cells association assay showed that the degree of target cell binding of this nanoparticles was much greater than that of common PEG-nanoparticles without bearing transferrin in vitro (Li et al., 2003). In this study, we selected paclitaxel as model drug and compared ATN's pharmacokinetics behavior, distribution, toxicity and anti-tumor efficacy in animal models with non-actively targeted PEG-nanoparticles (NTN) and current clinical formulation (paclitaxel injection). The result showed that this new formulation achieved a lot of advantages, especially, more effectively tumor regression through remarkably enhanced tumor accumulation of paclitaxel.
Section snippets
Materials
Paclitaxel (purity, >99%) and paclitaxel injection (No. 030911, 30 mg/5 ml) were purchased from Shanghai Hualian Pharmaceutical Co. Ltd. t-Boc-HNPEG 3400 was purchased from Shearwater Polymers Inc. (Huntsville, AL). Cyanoacetic acid (purity, 99%) and polyvinylalcohol (MW = 16,000) was obtained from Fluka (Buches, Switzerland). n-Hexadecanol, trifluoroacetic acid and human transferrin were purchased from Sigma (St. Louis, MO,USA). Mouse-anti-human transferrin antibody (MAB 033-19/1) and
Characteristics of ATN loading paclitaxel
The characteristics of ATN loading paclitaxel were summarized in Table 1. The paclitaxel was incorporated in ATN and NTN with a little different encapsulation efficiency by emulsion technique. ATN showed slightly low encapsulation efficiency than that of NTN. This result could be from that some paclitaxel was unadsorbed during transferrin was conjugated with NTN. In general, some of the drug could be adsorbed onto the surface of the nanoparticles by various forces such as Vander Wals forces
Acknowledgements
The work was partly supported by the National Natural Science Foundation of China, No. 30371691, and the National Basic Research Program of China (973 Program), No. 2004CB518802. Authors thank Prof. Zuming Shen and Dr. Yafang Wang for their excellent technical assistance in animal experiment.
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