Trastuzumab tagged chitosan nanovehicles as therapeutic carriers for cancer

Abstract

ABSTRACT newline newlineTargeting critical pathways in cancer cells with combination drugs becomes important because drug resistance is mitigated and drug efficacy is improved even at low concentrations. Docetaxel and 5-fluorouracil are chemotherapy drugs prescribed to patients with solid tumors. Although coated polymer nanovehicles can combat drug resistance by sequential drug release, this work proposes the encapsulation of docetaxel and 5-fluorouracil in chitosan nanovehicles. To further improve the targetability of the chitosan carriers, they are tagged with trastuzumab using crosslinker. Various techniques have been used to characterize the nanovehicles. HR-TEM images showed the formation of nanovehicles, the loading of drugs into chitosan nanovehicles, and the cross-linking of trastuzumab into chitosan nanovehicles. Experimental strategies were developed to evaluate the synergistic combination of drugs against AGS cell lines, delivered through nanovehicles. Drugs loaded in chitosan nanovehicles were found to synergistically inhibit AGS cell viability. The DPPH scavenging effect of drugs encapsulated in trastuzumab cross-linked chitosan nanovehicles was 55%, which is more effective than that of analogs containing only drugs. Changes were observed using acridine orange/ethidium bromide staining to enhance the synergistic efficacy of drugs loaded in nanocarriers in inducing apoptosis. Hemobiocompatibility analysis showed that the drugs in the formulation were less haemolytic than the drugs alone, which could be due to the sustained release of 5-fluorouracil. In vitro studies of AGS cell lines showed a synergistic effect of the combination with the antibody, which may be due to the anticancer effect of the nanocarriers in the treatment of cancer in several ways. A Sprague Dawley rat model of MNNG precancerous lesions was used in this study to confirm the efficacy of nanovehicles against gastric cancer. Changes in rat body weight, antioxidant parameters, and glycoprotein concentration in the gastric tissues of rats treated with nanovehicles showed the protective effect of nanovehicles against the progression of cancer lesions. Histopathological observation and ultrastructural changes of the stomach further confirmed the protective effect of antibody-conjugated nanovehicles. Immunohistochemical analysis performed to understand the expression of Bcl-2, PCNA, CD68 further confirmed the synergistic efficacy of nanovehicles against cancer development. Small animal in vivo imaging studies using rhodamine-tagged chitosan nanovehicles showed improved localization of the drug in the stomach, further confirming the targeted delivery of the nanocarriers. newlineKeywords: Chitosan nanovehicles; chemotherapeutic drugs; encapsulation; trastuzumab; conjugation; synergistic efficacy; anticancer effect; improved uptake newline newline