Improving Anti-Cancer Potentiality and Bioavailability of Gallic Acid by Designing Polymeric Nanocomposite Formulation

Abstract

Objective: In this study, we investigated the in vivo antitumor activity and pharmacokinetic characteristics of encapsulated GA-NC (gallic acid nanocomposite) in normal and hepatocellular carcinoma (HCC)-induced rats. Methods: Rats were distributed into 4 groups; negative control, HCC, gallic acid (GA), and GA-NC. Serum levels of alpha-fetoprotein (AFP), endoglin (ENG), heat shock protein-70 (HSP-70), pro-caspase 3, lipocalin-2 (LCN-2) and β-cell leukemia/lymphoma 2 (Bcl-2) were assayed by ELISA. The pharmacokinetic parameters for GA or GA-NC were determined by means of non-compartmental approach based on the serum– concentration profiles of free GA and GA-NC after oral administration. Also, histological procedures were used for examination of liver tissue sections. Results: Anaplastic changes in liver tissues were observed in untreated HCC group, as well as a significant increase in the serum AFP level. In addition, significant elevation in the serum ENG level as an angiogenic marker and the serum levels of the apoptotic mediators; HSP-70, Bcl-2 and pro-caspase 3 beside significant amplification in the serum inflammatory modulator, LCN-2 were recorded. Treatment with free GA or GA-NC markedly recovered the anaplastic changes in the rat liver tissues. In addition, they restored serum levels of AFP, ENG, HSP-70, Bcl-2, pro-caspase-3, and LCN-2. Pharmacokinetic analysis revealed that GA–NC displayed a characteristic sustained release profile with 4-fold increase in bioavailability in normal and HCC-induced rats. Conclusions: The results of this study suggest that encapsulation of GA into PLGA-CS-PEG enhances its oral bioavailability and anti-cancer activity. GA-NC may be a new therapeutic candidate for the mitigation of hepatocarcinogenesis.

Keywords: Gallic acid; gallic acid nanocomposite; anti-cancer; pharmacokinetic; in vivo; bioavailability.

Figure 1

Photomicrograph of Liver Section of (1A) Negative Control Group Showing Normal Histological Structure of Central Vein (cv) and Surrounding Hepatocytes in the Parenchyma. (H and E x 10), (1B) HCC group showing karyomegalic nuclei of the anaplastic hepatocytes with trabecular anaplastic arrangement and glandular pattern (1C).(H and E x 40), (1D) HCC + GA shows congestion in the portal vein, multiple newly formed bile ducts and inflammatory cells infiltration in between at the portal area as well as focal aggregations of mononuclear leucocytes inflammatory cells were detected in the hepatic parenchyma (1E) (H and E x 40), (1F) HCC + GA-NC showing congestion in the portal vein, newly formed bile ducts and inflammatory cells infiltration in between (HandE x 40).

Figure 2

Time Course of Gallic Acid (GA) in the Serum of Normal Rats after Oral Administration of () GA, () Gallic Acid Nanocomposite (GA-NC). GA was measured in serum after oral administration by HPLC. Each data point represents the mean± S.D. of 6 rats.

Figure 3

Time Course of Gallic Acid (GA) in the Serum of HCC-induced Rats after Oral Administration of () GA, () Gallic Acid Nanocomposite (GA-NC). GA was measured in serum after oral administration by HPLC. Each data point represents the mean± S.D. of 6 rats.