We designed a novel and simple protein delivery system for cancer immunotherapy : cholesteryl group-bearing polysaccharides, pullulan (CHP), complexed with antigen protein such as HER2/neu and NY-ESO-1 cancer/testis antigen. This unique hydrophobized polysaccharide helps soluble antigen protein to induce cellular immunity, both CD8⁺T cell and CD4⁺T cell dependent. Hence, such a novel vaccine may be of potential benefit to cancer therapy. Multi-institutional phase I clinical trials of CHP-HER2 and CHP-NY-ESO-1 have been conducted for patients with refractory cancer. Along with its safety evaluation, CD8⁺T cell and/or CD4⁺T cell dependent specific immune responses became detectable in vaccinated patients. Clinical responses were also observed in some patients.

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Drug delivery technologies have been applied to existing anticancer drugs for greater efficacy and favorable safety profiles compared with existing formulations.
LHRH analog and liposomal doxorubicin are incorporated into standard cancer chemotherapy. Albumin bound paclitaxel nanoparticle has been developed to reduce the potential disadvantage of existing formulation for patients and clinical facilities. In this article physicochemical and clinical features of these drug formulations are discussed.

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Cisplatin is used for the standard treatment for lung cancer, stomach cancer, and urothelial cancer. However, it is necessary to discontinue treatment with cisplatin due to its adverse effects such as nephrotoxicity and neurotoxicity. In order to reduce the toxicity and increase the efficacy, increasing intra-tumoural cisplatin levels using drug delivery system is seemed to be the valuable approarch. NC-6004 was designed as a novel delivery system of cisplatin by Kataoka. It retains the activity, but avoids the nephrotoxicity and neurotoxicity observed with cisplatin. Phase I study of NC-6004 in patients with advanced cancer was conducted in UK.
Epirubicin was used for the pH-sensitive micelle as same as doxorubicin conjugated type invented by Kataoka. Antitumor effect of pH-sensitive epirubicin micelle was superior to epirubicin solution in vivo animal model.
Many protein drugs such as interferon, interleukin, granulocyte colony stimulating factor (G-CSF) and growth factor need to have stability in the bloodstream in order to have therapeutic efficacy. The protein micelle system was established using block-copolymer modification techniques. G-CSF micelle showed the sustained release property as same as PEGylated G-CSF. It seems that protein micelle technology is suitable for the bio-similar drugs and the protein having short half-life in blood.

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Polymeric micelles were expected to increase the accumulation of drugs in tumor tissues utilizing the EPR effect and to incorporate various kinds of drugs into the inner core by chemical conjugation or physical entrapment with relatively high stability. The size of the micelles can be controlled within the diameter range of 20 to 100 nm, to ensure that the micelles do not pass through normal vessel walls; therefore, a reduced incidence of the side effects of the drugs may be expected. There are several anticancer agent-incorporated micelle carrier systems under clinical evaluation. NK105, paclitaxel (PTX) -incorporating micelle, facilitated prolonged systemic exposure in plasma in Japanese phase I study. Tri-weekly 1-hr infusion of NK105 was feasible and well tolerated, with antitumor activity. A phase II study of NK105 has been terminated. A phase I study of NC-6004, cisplatin (CDDP) -incorporating micelle was conducted in the UK. Nephrotoxicity was significantly reduced and gastrointestinal toxicity was also mild. Two independent phase I trials of NK012, an SN-38 loaded polymeric micelle, were conducted successfully in Japan and the USA. NK012 was well tolerated and phase II studies of NK012 are now underway in both countries.

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Liposomes have some advantages as delivery carriers of drug, antigen or gene. Newly developed liposomes, coating with amphipathic PEG derivatives, are not readily taken up by the macrophages in the RES and hence stay in the circulation for a relatively long period of time. PEG-liposome can take advantage of the EPR effect (enhanced permeability and retention effect) for efficient targeting binding in the tumor. For the active targeting following the passive targeting to the solid tumor tissue, transferrin (TF) was conjugated to prepare TF-PEG-liposomes. TF-PEG liposomes showed a prolonged residence time in the circulation and low uptake by the RES in tumor-bearing mice, resulting in enhanced accumulation of drug into the solid tumor tissue. In a more important thing, TF-PEG-liposomes could be internalized into tumor cells with receptor mediated endocytosis following extravasation into tumor tissue. Based on above-mentioned liposome technology, novel liposomal bubbles (Bubble liposomes) containing the ultrasound imaging gas, perfluoropropane were developed. Bubble liposomes could deliver plasmid DNA to various cell types in vitro by combination with ultrasound without cytotoxicity. This combination could effectively deliver plasmid DNA into mouse liver in vivo, more effectively than conventional lipofection. We conclude that Bubble liposomes are unique and efficient gene delivery carriers in vitro and in vivo. In this review, the potential advantages of using TF-PEG-liposome and Bubble liposome for drug delivery system will be introduced.

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