**1. Introduction**

186 Liver Tumors

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of Hepatic Blood Flow Occlusion on Thermal Injuries Produced in Cirrhotic Livers.

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. More than 500 000 new cases are currently diagnosed yearly, with an age-adjusted worldwide incidence of 5.5–14.9 per 100 000 population (Jemal et al., 2011). Doxorubicin remains the first line of treatment for liver cancer ever since its discovery in 1971 (Yoshikawa & Kitaoka, 1971). Unfortunately, clinical effectiveness of this class of drugs is limited by cumulative cardiotoxicity which occurs in significant percentage of patients at cumulative dose in the range 450-600 mg/m2 (Ganz et al., 1993). Therefore, various strategies have been developed to reduce cardiotoxicity of doxorubicin and its analogues (Haley & Frenkel, 2008). Commercialized doxorubicin has high cytotoxicity, good solubility and high affinity to nuclear (Viale & Yamamoto, 2008). There is no need to improve its ability to penetrate cell membrane and accumulation into cell nuclear. The aim of delivery techniques is to alter its in vivo distribution, enhance its deposition in the liver tumor sites and reduce its cardiotoxicity. Formulations of doxorubicin should have the ability to specifically release the drug in response to the tumor micro-environment.

Doxorubicin can insert in the double strand of DNA and preferentially bind to doublestranded 5'-GC-3' or 5'-CG-3' to form tightly coupled complex without chemical bond links (Vicent, 2007). Once the DNA was digested, the doxorubicin can be released. Cationic polymers are often used as carriers for the DNA drugs' delivery because they can combine DNA to form nanoscale particles by the interaction between their positive charge and the negative charge on the DNA chain (Bodley et al., 1989). Upon these two aspects, we developed a nanoscale formulation of doxorubicin. Doxorubicin was complexed into polyGC double-strand DNA fragments to form the DOX-polyGC intercalation. After that, the DOX-polyGC intercalation was combined by a bio-degradable cationic polymer, cationic gelatin, to form nanoscale particles. Cationic gelatin can be effectively digested by gelatinase (GA) that is a mixture of two kinds of matrix metalloproteinase (MMP) highly expressed by the tumor tissue (Eliyahu, 2005). This makes the complex composed by cationic gelatin, DNA and doxorubicin (CPX1) can be specifically digested and release the doxorubicin in tumor sites (Figure 1). To avoid the accumulation into the liver which also produces gelatinase in a relatively high level (Emonard & Grimaud, 1990), a pH-sensitive material, histamine-modified alginate (His-alginate) was used to cover CPX1 to form CPX2. His-alginate has a pKa of about 6.9 which shows a cationic state when pH < 6.9 and an anionic state when pH > 6.9. His-alginate combined CPX1 at physiological pH (7.2) via its anion interact with the cation on the surface of CPX1. In tumor micro-environment, the pH varied from 6.2-6.7 according to different physical states. At such a pH, Hisalginate turned it anionic state to a cationic one and dissociated from CPX2. To enhance the ability of CPX2 to escape from the reticuloendothelial system, PEG 2000 was conjugated to His-alginate to form PEG-His-alginate (PHA). The construct scheme was shown in Figure 1.

Fig. 1. Fabrication scheme of CXP1 and CPX2.
