A large quantity of FA-functioned polymeric NPs loaded with SPIO was developed,113C116 which mediates by FACFRs interaction; hence, these nanosystems could specifically accumulate in the tumor tissue and inhibit the growth of tumor. Biotin Biotin, also known as vitamin H, vitamin B7, or coenzyme R, is one of the water-soluble B complex vitamin families and is a growth promotor at the cellular level.118 It is reported that this biotin receptors are overexpressed more than the FRs in various cancer cells such as leukemia, colon, mastocytoma, lung, renal, and breast cancer cells.118 A study demonstrated that modification of drug delivery with biotin is an effective pattern to enhance cell specificity against the cancer cells overexpressed with biotin receptors around the cell surfaces and to accelerate the internalization of the drug delivery into the targeted cancer cells through receptor-mediated endocytosis.119 To verify the potential value of biotin for targeted liver neoplasms, Mishra and Jain120 designed biotin-modified erythrocytes loaded with MTX by combining with (licorice).217 It is demonstrated that this GA and glycyrrhizin could mediate the active hepatic-targeting drug delivery system through GA receptor and glycyrrhizin receptor, respectively.218C220 In 1991, Negishi et al221 confirmed that Topotecan HCl (Hycamtin) the quantity of GA binding sites was higher than that of glycyrrhizin binding sites, that is to say, the GA could be more effective than glycyrrhizin to HCC. by the co-delivery of BCL-2 siRNA, indicating that co-loading siRNA and chemotherapeutic agent in a targeted drug delivery enables simultaneous delivery of specific siRNA and drug into hepatoma cell with synergistic effect in antitumor activity, which was also proved by another study.101 Co-delivering two chemotherapeutic agents in a drug delivery is alternative strategy to overcome MDR of HCC. For example, multifunctional DOX loaded-folate-chitosan self-assembly micellar NPs co-delivered pyrrolidinedithiocarbamate, a NF-B inhibitor, to achieve specific targeting and to surmount the DOX MDR.105 Tumor metastasis remains the major obstacle for the improvement in the long-term survival after HCC resection.106,107 Intrahepatic metastasis is the most frequent, followed by extrahepatic pulmonary metastasis.108 NP-mediated targeted therapy is a promising antimetastatic strategy for pulmonary metastasis. FA and paclitaxel (PTX) made up of composite micelles (FA-M[PTX]) were fabricated by co-assembling the ligand FA polymer conjugate and chemotherapeutic agent PTX polymer conjugate.109 Compared with M[PTX] and free MTX with equivalent dose of PTX, the pulmonary metastasis in intravenously injected murine hepatoma 22 bearing BALB/c mice models was efficiently inhibited and Topotecan HCl (Hycamtin) the survival Topotecan HCl (Hycamtin) time was significantly prolonged by FA-M[PTX]. Multifunctional delivery systems that carry therapeutic and diagnostic imaging brokers with FA are emerging concept for effective targeted therapy. The diagnostic imaging brokers contain fluorophores, quantum dots (QDs),110 small-molecule paramagnetic brokers,111,112 SPIO,113C117 and so forth. Wang et al110 designed a smart multifunctional polymeric micelle for targeted therapy of HCC. The pH-sensitive polymeric vehicle turns PTX release off at neutral environment but on inside acidic lysosomes, and the QD encapsulation tracks pH-tunable drug release behavior and monitors the therapeutic effect. Moreover, the targeting capacity of the micelle was enhanced through the specific conversation and internalization with high affinity between ligand FA on micelle and FRs on human hepatoma cells, which was proved by cellular uptake in vitro and tumor growth inhibition in vivo. Multifunctional NPs encapsulated with SPIO is usually another approach to monitor the tumor progression using magnetic resonance imaging (MRI). A large quantity of FA-functioned polymeric NPs loaded with SPIO was developed,113C116 which mediates by FACFRs conversation; hence, these nanosystems could specifically accumulate in the tumor tissue and inhibit the growth of tumor. Biotin Biotin, also known as vitamin H, vitamin B7, or coenzyme R, is one of the water-soluble B complex vitamin families and is a growth promotor at the cellular level.118 It is reported that this biotin receptors are overexpressed more than the FRs in various cancer cells such as leukemia, colon, mastocytoma, lung, renal, and breast cancer cells.118 A study demonstrated that modification of drug delivery with biotin is an effective pattern to enhance cell specificity against the cancer cells overexpressed with biotin receptors around the cell surfaces and to accelerate the internalization of the drug delivery into the targeted cancer cells through receptor-mediated endocytosis.119 To verify the potential value of biotin for targeted liver neoplasms, Mishra and Jain120 designed biotin-modified erythrocytes loaded with MTX by combining with (licorice).217 It is demonstrated that this GA and glycyrrhizin could mediate the active hepatic-targeting drug delivery system through GA receptor and glycyrrhizin receptor, respectively.218C220 In 1991, Negishi et al221 confirmed that the quantity of GA binding sites was higher than that of glycyrrhizin binding sites, that is to say, the GA could be more effective than glycyrrhizin to HCC. Thus, the FKBP4 GA has been developed in targeted therapy for HCC as a ligand, which was summarized in a review.218 In a recent work, the capacity of the GA to HCC was also proved through a drug and gene codelivery carrier modified with GA.219 The drug concentration and gene transfection efficiency of GA-modified carrier was remarkably higher than that of GA-modified carrier adding free GA. Moreover, the GA-modified Topotecan HCl (Hycamtin) carrier possessed much better antitumor efficacy on xenograft liver tumor. All results indicate that GA as a ligand plays an important Topotecan HCl (Hycamtin) role in enhancing HCC-targeting efficacy through active targeting. In the aforementioned section, the EGFR was described as a targeting site to match antibodies for HCC. Epidermal growth factor (EGF), derived from the cleavage of prepro-EGF and generated primarily in kidney in humans, can bind with EGFR as well, which promotes embryonic development and stem cell regeneration and regulates ion transport.222 To resolve.