| Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide andcauses more than500,000deaths annually[1]. In the United States, the incidence of HCChas increased by more than90%in the past three decades. Despite great achievementshave been obtained in HCC diagnosis and therapy, the morality rate remains high,especially for advanced HCC when the disease is usually diagnosed. Adriamycin (ADR)has been widely used in the therapy of advanced hepatocellular carcinoma. However, theoverall response rates are low, and ADR does not seem to prolong survival[2]. Furthermore,a major limitation for the use of ADR is the development of cardiotoxicity[3], which limitsadmistration exceeding an accumulated dose of about550mg/m2.Nanotechnology has been extensively exploited to improve conventional cancerchemotherapy. The nanocarriers-based therapeutic products are expected to reduce the sideeffects of chemotherapeutics, protect the drug from premature degradation, substantiallyalter the pharmacokinetics and increase drug concentration in tumors. In the past twodecades, a large number of nanocarriers-based therapeutic products have entered clinicaldevelopment or been approved for clinical use. Among these nanocarriers, liposomes andnanoparticles of biodegradable polymers are two dominant classes, accounting for themajority of the clinically approved products. Liposomes, the spherical lipid vesicles withsingle or multiple lipid bilayers, have been widely applicated because of their highbiocompatibility, favorable pharmacokinetic profile, ease of surface modification and longcirculation time after being surface modified with polyethylene glycol (PEG). However,liposomes are limited in clinic use by their uncontrollable drug release, instability instorage and insufficient drug loading. Nanoparticles of biodegradable polymers arefeatured by their controlled drug release manner, stability in storage and capability to carryhighly insoluble drug with high loading efficiency. Yet the biocompatibility ofnanoparticles formed by most synthetic polymers is not as high as liposomes. Moreover,nanoparticles have shown moderate circulation half-lives compared with liposomes. It isthus ideal if any novel lipid-polymer hybrid nanoparticles could be fabricated throughcombining the advantages and overcoming the disadvantages of the two types of drugnanocarriers. Numerous studies reported that epidermal growth factor receptor (EGFR)overexpression occurs frequently in HCC, and in some cases has been correlated with poorprognosis, suggesting that EGFR is a potential target for HCC therapy. More importantly,EGFR is an internalizing antigen and targeting of nanoparticles to internalizing antigens results in delivery of much more drugs to the cytoplasm or nucleus compared withtargeting to noninternalizing antigens[5,6]. It is noteworthy that anti-EGFR antibody hasbeen widely applied to the various nanocarriers to realize sustained, controlled and targeteddrug delivery for EGFR-positive HCC therapy.To obtain a robust drug delivery system for HCC targeted chemotherapy, wesuccessfully synthesized and characterized ADR loaded polymer-lipid hybrid nanoparticlesconjugated with anti-EGFR antibody (PLNP-Mal-EGFR). The nanoparticles combined thedesirable characteristics of liposomes and polymer-based nanoparticles, while eliminatingsome of their disadvantages. Furthermore, the nanoparticles were characterized by DLS(dynamic light scattering) for in vitro stability, size and size distribution, TEM for surfacemorphology and structure, and fluorescence spectroscopy for drug encapsulation efficiencyand in vitro drug release kinetics. Three HCC cell lines with different EGFR expressionlevels were chosen to evaluate the cellular uptake and cytotoxicity. And then, the cytotoxiceffects of nanoparticles on SP cells[6], which may be source of the drug assistance of tumorand are enriched with CSCs, were also evaluated. Finally, we evaluate the effect ofnanoparticles in tumor-bearing mice. |
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