Yoo Shin Kim

Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy

To prepare a water-insoluble camptothecin (CPT) delivery carrier, hydrophobically modified glycol chitosan (HGC) nanoparticles were constructed by chemical conjugation of hydrophobic 5beta-cholanic acid moieties to the hydrophilic glycol chitosan backbone. Insoluble anticancer drug, CPT, was easily encapsulated into HGC nanoparticles by a dialysis method and the drug loading efficiency was above 80%. CPT-encapsulated HGC (CPT-HGC) nanoparticles formed nano-sized self-aggregates in aqueous media (280-330 nm in diameter) and showed sustained release of CPT for 1 week. Also, HGC nanoparticles effectively protected the active lactone ring of CPT from the hydrolysis under physiological condition, due to the encapsulation of CPT into the hydrophobic cores in the HGC nanoparticles. The CPT-HGC nanoparticles exhibited significant antitumor effects and high tumor targeting ability towards MDA-MB231 human breast cancer xenografts subcutaneously implanted in nude mice. Tumor growth was significantly inhibited after i.v. injection of CPT-HGC nanoparticles at doses of 10 mg/kg and 30 mg/kg, compared to free CPT at dose of 30 mg/kg. The significant antitumor efficacy of CPT-HGC nanoparticles was attributed to the ability of the nanoparticles to show both prolonged blood circulation and high accumulation in tumors, as confirmed by near infrared (NIR) fluorescence imaging systems. Thus, the delivery of CPT to tumor tissues at a high concentration, with the assistance of HGC nanoparticles, exerted a potent therapeutic effect. These results reveal the promising potential of HGC nanoparticles-encapsulated CPT as a stable and effective drug delivery system in cancer therapy.

Antitumor efficacy of cisplatin-loaded glycol chitosan nanoparticles in tumor-bearing mice

To make a tumor targeting nano-sized drug delivery system, biocompatible and biodegradable glycol chitosan (M(w)=250 kDa) was modified with hydrophobic cholanic acid. The resulting hydrophobically modified glycol chitosans (HGCs) that formed nano-sized self-aggregates in an aqueous medium were investigated as an anticancer drug carrier in cancer treatment. Insoluble anticancer drug, cisplatin (CDDP), was easily encapsulated into the hydrophobic cores of HGC nanoparticles by a dialysis method, wherein the drug loading efficiency was about 80%. The CCDP-encapsulated HGC (CDDP-HGC) nanoparticles were well-dispersed in aqueous media and they formed a nanoparticles structure with a mean diameter about 300-500 nm. As a nano-sized drug carrier, the CDDP-HGC nanoparticles released the drug in a sustained manner for a week and they were also less cytotoxic than was free CDDP, probably because of sustained release of CDDP from the HGC nanoparticles. The tumor targeting ability of CDDP-HGC nanoparticles was confirmed by in vivo live animal imaging with near-infrared fluorescence Cy5.5-labeled CDDP-HGC nanoparticles. It was observed that CDDP-HGC nanoparticles were successfully accumulated by tumor tissues in tumor-bearing mice, because of the prolonged circulation and enhanced permeability and retention (EPR) effect of CDDP-HGC nanoparticles in tumor-bearing mice. As expected, the CDDP-HGC nanoparticles showed higher antitumor efficacy and lower toxicity compared to free CDDP, as shown by changes in tumor volumes, body weights, and survival rates, as well as by immunohistological TUNEL assay data. Collectively, the present results indicate that HGC nanoparticles are a promising carrier for the anticancer drug CDDP.

Tumor-homing multifunctional nanoparticles for cancer theragnosis: Simultaneous diagnosis, drug delivery, and therapeutic monitoring.

Theragnostic multifunctional nanoparticles hold great promise in simultaneous diagnosis of disease, targeted drug delivery with minimal toxicity, and monitoring of treatment. One of the current challenges in cancer treatment is enhancing the tumor-specific targeting of both imaging probes and anticancer agents. Herein, we report tumor-homing chitosan-based nanoparticles (CNPs) that simultaneously execute cancer diagnosis and therapy (cancer theragnosis). These CNPs are unique for their three distinctive characteristics, such as stability in serum, deformability, and rapid uptake by tumor cells. These properties are critical in increasing their tumor targeting specificity and reducing their nonspecific uptake by normal tissues. To develop these CNPs into novel theragnostic nanoparticles, we labeled them with Cy5.5, a near-infrared fluorescent (NIRF) dye, for imaging and also loaded them with paclitaxel (PTX-CNPs), an anticancer drug, for cancer treatment. Cy5.5 labeled PTX-CNPs exhibited significantly increased tumor-homing ability with low nonspecific uptake by other tissues in SCC7 tumor-bearing mice. Theragnostic nanoparticles, Cy5.5 labeled PTX-CNPs, are highly useful for simultaneous diagnosis of early-stage cancer and drug delivery.

Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy.

Antiangiogenic peptide drugs have received much attention in the fields of tumor therapy and tumor imaging because they show promise in the targeting of integrins such as alpha(v)beta(3) on angiogenic endothelial cells. However, systemic antiangiogenic peptide drugs have short half-lives in vivo, resulting in fast serum clearance via the kidney, and thus the therapeutic effects of such drugs remain modest. In this study, we prepared self-assembled glycol chitosan nanoparticles and explored whether this construct might function as a prolonged and sustained drug delivery system for RGD peptide, used as an antiangiogenic model drug in cancer therapy. Glycol chitosan hydrophobically modified with 5beta-cholanic acid (HGC) formed nanoparticles with a diameter of 230 nm, and RGD peptide was easily encapsulated into HGC nanoparticles (yielding RGD-HGC nanoparticles) with a high loading efficiency (>85%). In vitro work demonstrated that RGD-HGC showed prolonged and sustained release of RGD, lasting for 1 week. RGD-HGC also inhibited HUVEC adhesion to a beta ig-h3 protein-coated surface, indicating an antiangiogenic effect of the RGD peptide in the HGC nanoparticles. In an in vivo study, the antiangiogenic peptide drug formulation of RGD-HGC markedly inhibited bFGF-induced angiogenesis and decreased hemoglobin content in Matrigel plugs. Intratumoral administration of RGD-HGC significantly decreased tumor growth and microvessel density compared to native RGD peptide injected either intravenously or intratumorally, because the RGD-HGC formulation strongly enhanced the antiangiogenic and antitumoral efficacy of RGD peptide by affording prolonged and sustained RGD peptide delivery locally and regionally in solid tumors.

Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy

PurposeAnitangiogenic and apoptotic properties of a novel chemically modified heparin derivative with low anticoagulant activity were evaluated on the experimental in vitro and in vivo model.Materials and MethodsHeparin-lithocholate conjugate (HL) was initially synthesized by covalently bonding lithocholate to heparin. Folate-HL conjugate (FHL) was further synthesized by conjugating folate to HL. Antiangiogenic and apoptotic abilities of HL and FHL were characterized in vitro and in vivo experimentations.ResultsCompared to unmodified heparin, both HL and FHL represented a low anticoagulant activity (38 and 28%, respectively). HL and FHL maintained antiangiogenic activity even further modification from the results of Matrigel plugs assay. FHL specifically induced apoptosis on KB cells having highly expressed folate receptor after cellular internalization. Both administered HL and FHL had similar antiangiogenic activity and inhibitory effect on tumor growth in vivo although FHL induced higher apoptosis on tumor tissues.ConclusionsIn vivo tumor growth inhibition was possibly due to the decrease of vessel density and apoptotic cell death, although antiangiogenic effect of FHL seemed more actively affected on growth inhibition than apoptotic potential in vivo system. Thus, Low anticoagulant FHL having antiangiogenic and apoptotic properties would provide benefits for the development of a new class of anticancer agent.

Self-Assembled Nanoparticles of Bile Acid-Modified Glycol Chitosans and Their Applications for Cancer Therapy

This review explores recent works involving the use of the self-assembled nanoparticles of bile acid-modified glycol chitosans (BGCs) as a new drug carrier for cancer therapy. BGC nanoparticles were produced by chemically grafting different bile acids through the use of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The precise control of the size, structure, and hydrophobicity of the various BGC nanoparticles could be achieved by grafting different amounts of bile acids. The BGC nanoparticles so produced formed nanoparticles ranging in size from 210 to 850 nm in phosphate-buffered saline (PBS, pH=7.4), which exhibited substantially lower critical aggregation concentrations (0.038-0.260 mg/mL) than those of other low-molecular-weight surfactants, indicating that they possess high thermodynamic stability. The BGC nanoparticles could encapsulate small molecular peptides and hydrophobic anticancer drugs with a high loading efficiency and release them in a sustained manner. This review also highlights the biodistribution of the BGC nanoparticles, in order to demonstrate their accumulation in the tumor tissue, by utilizing the enhanced permeability and retention (EPR) effect. The different approaches used to optimize the delivery of drugs to treat cancer are also described in the last section.

Evaluation of the anti-tumor effects of paclitaxel-encapsulated pH-sensitive micelles

We evaluated the efficacy of pH-sensitive micelles, formed by methoxy poly(ethylene glycol)-b-poly(β-amino ester) (PEG-PAE), as carriers for paclitaxel (PTX), a drug currently used to treat various cancers. PTX was successful encapsulated by a film hydration method. Micelles encapsulated more than 70% of the PTX and the size of the PTX-encapsulated micelles (PTX-PM) was less than 150 nm. In vitro experiments indicated that the micelles were unstable below pH 6.5. After encapsulation of PTX within the micelles, dynamic light scattering (DLS) studies indicated that low pH had a similar demicellization effect. An in vitro release study indicated that PTX was slowly released at pH 7.4 (normal body conditions) but rapidly released under weakly acidic conditions (pH 6.0). We demonstrated the safety of micelles from in vitro cytotoxicity tests on HeLa cells and the in vivo anti-tumor activity of PTX-PM in B16F10 tumor-bearing mice. We concluded that these pH-sensitive micelles have potential as carriers for anti-cancer drugs.

Tumoral Accumulation of Long-Circulating, Self-Assembled Nanoparticles and Its Visualization by Gamma Scintigraphy

The enhanced permeability and retention (EPR) effect is used extensively for the passive targeting of many macromolecular drugs for tumors. Indeed, the EPR concept has been a gold standard in polymeric anticancer drug delivery systems. This study investigated the tumoral distribution of self-assembled nanoparticles based on the EPR effect using fluorescein and radio-labeled nanoparticles. Self-assembled nanoparticles were prepared from amphiphilic chitosan derivatives, and their tissue distribution was examined in tumor-bearing mice. The size of the nanoparticles was controlled to be 330 nm, which is a size suited for opening between thedefective endothelial cells in tumors. The long-circulating polymer nanoparticles were allowed to gradually accumulate in the tumors for 11 days. The amount of nanoparticles accumulated in the tumors was remarkably augmented from 3.4%ID/g tissue at 1 day to 25.9%ID/g tissue at 11 days after i.v. administration. The self-assembled nanoparticles were sustained at a high level throughout the 14 day experimental period, indicating their long systemic retention in the blood circulation. The γ-images provided clear evidence of selective tumor localization of the131 I-labeled nanoparticles. Confocal microscopy revealed the fluorescein-labeled nanoparticles to be preferentially localized in the perivascular regions, suggesting their extravasation to the tumors through the hyperpermeable angiogenic tumor vasculature. This highly selective tumoral accumulation of nanoparticles was attributed to the leakiness of the blood vessels in the tumors and their long residence time in the blood circulation.