Drug Delivery to Hepatocellular Carcinomas

Hepatocellular carcinomas (HCCs) are generally identified clinically at an advanced stage, usually in combination with cirrhosis. Though optimal, surgical resection is associated with a high rate of recurrence. Approaches to prevent recurrence, like chemoembolization after surgery, have not proven to be beneficial. Both doxorubicin and cisplatin are frequently used in the treatment of these carcinomas, but the overall response rates are low and neither approach seems to prolong the survival. Newly emerging agents with promising results include 90Y microspheres, antiangiogenesis agents, inhibitors of growth factors and their receptors, and K vitamins.156

HCC is known to be chemoresistant to anti-cancer drugs due to the expression of multi-drug resistant (MDR) transporters. Doxorubicin loaded into the PACA nanoparticles enhanced the efficiency of treatment in the M5076 murine hepatic tumor metastasis in mice.91 After intravenous injection, the doxorubicin-loaded PBCA nanoparticles resulted in higher hepatic concentrations in tumor-bearing mice. Histology of the mouse liver after the intravenous injection of the nanoparticle formulation revealed greater accumulation of nanoparticles in the Kupfer cells but not in the tumor cells.123 This was supposed to be the result of macrophage uptake and subsequent capture by the Kupfer cells, of the nanoparticle formulation owing to the hydrophobicity of the nanoparticles, and then the drug release close to the tumor cells in the liver. To better understand the role of macrophages in delivering the nanoparticle-bound doxorubicin to the tumor cells, a co-culture system was developed consisting of two compartments separated by a porous polyester membrane (Transwell clear insert).126 The results were compared with the control experiments involving direct incubation of drug/formulations with the tumor cells. The M5076 cells were seeded into the lower compartment, whereas the J774.A1 macrophage monocyte cells were placed on the top of the membrane. The doxorubicin and doxorubicin-loaded isobutylcyanoacrylate nanoparticle formulation were added to the upper compartment containing macrophages. The doxorubicin and nanoparticle formulation showed a 5-fold increase in IC50 of M5076 tumor cells in the co-culture system. In some groups of experiments, the recombinant mouse interferon-g (IFN-g) was added to the macrophage compartment before the addition of the formulation to activate the macrophages. This would result in the release of cytotoxic factors such as IFN-a and nitric oxide.157 Doxorubicin and nanoparticle formulation were found to be more cytotoxic when the macrophages were activated by IFN-g. In fact, this would probably be a result of a synergistic effect of the cytotoxic factors, especially nitric oxide released by the activated macrophages and the nanoparticle formulation because the role of antitumor factors in the inhibition of tumors both in vitro and in vivo has been well documented.158,159 This co-culture system gives a clear indication of the role that macrophages play after intravenous injection in enhancing the cytotoxicity of the doxorubicin-loaded PACA nanoparticle formulation and its efficacy in liver tumor.

Recently, Barraud et al.160 compared the antitumor efficacy of Dox-loaded PIHCA nanoparti-cles with free doxorubicin, both in vitro and in vivo, in HCC-bearing transgenic mice overexpressing the mdr1 and mdr3 genes. The 50% inhibition concentration (IC50) of doxorubicin in vitro on different human hepatoma cell lines decreased with the nanoparticle formulation, compared to that of free Dox. Dox-loaded nanoparticles showed an enhanced MDR reversal in these cells.

Mitoxantrone-loaded PBCA nanoparticles showed higher tumor concentration after intravenous injection in the B-16 melanoma-bearing mice.89 These nanoparticles have also shown higher efficacy in the treatment of B-16 melanoma.28 The efficacy of mitoxantrone-loaded PBCA nano-particles after intravenous administration was also tested in heterotopic and orthotopically transplanted human HCC-bearing mice.161 The efficacy of the mitoxantrone-loaded nanoparticles was compared with that of free mitoxantrone and doxorubicin. In orthotopically transplanted mice, all three preparations produced a similar effect. Microscopic examination revealed that the mitoxantrone-loaded nanoparticles showed enhanced antitumor activity in heterotopically transplanted mice, which was supported by a low tumor cell proliferation. The nanoparticles also did not show any signs of toxicity of the heart, spleen, lung, and kidney, indicating their effectiveness in tumor therapy and that the fact that they had overcome the adverse effects associated with the anti-cancer agents.

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