Jinhyang Choi

Use of macrophages to deliver therapeutic and imaging contrast agents to tumors

Drug targeting to tumors with limited toxicity and enhanced efficacy of drug is one of the important goals for cancer treatment pharmaceutics. Monocytes/macrophages are able to migrate to tumor sites across the blood barriers by acting as Trojan horses carrying drug cargoes. Taking this advantage, we have intended to develop an efficient administration system using a biologically active carrier of mouse peritoneal macrophage bearing liposomal doxorubicin (macrophage-LP-Dox). We expect that this system could improve the cancer therapeutic efficacy through deeper penetration into tumor even hypoxic region behind tumor blood vessel. We first confirmed that macrophages containing iron oxides could migrate and infiltrate into tumors effectively by MR imaging. Next, we showed that doxorubicin (Dox) encapsulated with liposomes (LP-Dox) was successfully loaded into macrophages, in which the biological activity of macrophage and cytotoxicity of Dox against tumor cells were well preserved. Delivery of Dox into tumor tissue by systemic administration of macrophage-LP-Dox was verified in both subcutaneous and metastasis xenograft tumor models. Importantly, the effective inhibition of in vivo tumor growth was proved with this system. Our results provide the feasibility of macrophages-LP-drug as an active biocarrier for the enhancement of therapeutic effects in cancer treatment and open new perspectives for the active delivery of drugs.

Multifunctional hollow gold nanoparticles designed for triple combination therapy and CT imaging.

Hollow gold nanoparticles (HGNP) are a novel class of hybrid metal nanoparticles whose unique optical and morphological properties have spawned new applications including more effective cancer therapy. The shell thickness of HGNPs can tune the surface plasmon resonance to the near infrared light, resulting in photothermal ablation of tumors with optimal light penetration in tissue. The hollow cavity within a HGNP is able to accommodate a high payload of chemotherapeutic agents. They have also been used for enhancing radiosensitization in tumors during radiotherapy due to the high X-ray absorption capability of gold particles. However, no report has yet been published that utilize HGNPs for the triple combination therapy and CT imaging. In this study, we synthesized HGNPs which exhibit better response to radiation for therapy and imaging and demonstrated the effects of combined chemotherapy, thermal and radiotherapy. This combination strategy presented delayed tumor growth by 4.3-fold and reduced tumors weight by 6.8-fold compared to control tumors. In addition, we demonstrated the feasibility of HGNP as a CT imaging agent. It is expected that translating these capabilities to human cancer patients could dramatically increase the antitumor effect and potentially overcome resistance to chemotherapeutic agents and radiation.

Immunocytes as a biocarrier to delivery therapeutic and imaging contrast agents to tumors

Radiotherapy for cancer treatment has been used for primary or adjuvant treatment in many types of cancer, and approximately half of all cancer patients are undergoing radiation. However, ionizing radiation exposure induces genetic alterations in cancer cells and results in recruitment of monocytes/macrophages by triggering signals released from these cells. Using this characteristic of monocytes/macrophages, we have attempted to develop a biocarrier loading radiosensitizing anticancer agents that can lead to enhance the therapeutic effect of radiation in cancer treatment. The aim of this study is to demonstrate the proof of this concept. THP-1 labeled with Qdot 800 or iron oxide (IO) effectively migrated into tumors of subcutaneous mouse model and increased recruitment after ionizing radiation. Functionalized liposomes carrying a radiosensitizing anticancer agent, doxorubicin, are successfully loaded in THP-1 (THP-1-LP-Dox) with reduced cytotoxicity, and THP-1-LP-Dox also was observed in tumors after intravenous administration. Here, we report that monocytes/macrophages as a biocarrier can be used as a selective tool for amplification of the therapeutic effects on radiotherapy for human cancer treatment.

Ibulocydine sensitizes human cancers to radiotherapy by induction of mitochondria-mediated apoptosis.

BACKGROUND AND PURPOSE Ibulocydine (IB), a novel prodrug of CDK inhibitor, has been reported to have anti-cancer effect in human hepatoma cells. In order to address its feasibility as a radiosensitizer to improve radiotherapeutic efficacy for human cancers, this study was designed. MATERIAL AND METHODS Human cancer cells of lung and colon were treated with IB and/or radiotherapy (RT). The cellular effects were assessed by CCK-8, clonogenic, flow cytometric, and western blotting assays. In vivo radiotherapeutic efficacy was evaluated using the xenograft mouse model. RESULTS Combined treatment of IB and RT significantly reduced viability and survival fraction of the cells. Apoptotic cell death accompanied with activation of caspases, decrease in Bcl-2/Bax expression, loss of mitochondrial membrane potential (MMP) leading to release of cytochrome c into cytosol was observed. Recovery of Bcl-2 expression level by introducing Bcl-2 expressing plasmid DNA compromised the loss of MMP and apoptosis induced by IB and RT. In vivo therapeutic efficacy of combined treatment was verified in the xenograft mouse model, in which tumor growth was markedly delayed by RT with IB. CONCLUSIONS IB demonstrated the property of sensitizing human cancer cells to RT by induction of mitochondria-mediated apoptosis, suggesting that IB deserves to be applied for chemoradiotherapy.

Nanoparticulated docetaxel exerts enhanced anticancer efficacy and overcomes existing limitations of traditional drugs.

Nanoparticulation of insoluble drugs improves dissolution rate, resulting in increased bioavailability that leads to increased stability, better efficacy, and reduced toxicity of drugs. Docetaxel (DTX), under the trade name Taxotere™, is one of the representative anticancer chemotherapeutic agents of this era. However, this highly lipophilic and insoluble drug has many adverse effects. Our novel and widely applicable nanoparticulation using fat and supercritical fluid (NUFS™) technology enabled successful nanoscale particulation of DTX (Nufs-DTX). Nufs-DTX showed enhanced dissolution rate and increased aqueous stability in water. After confirming the preserved mechanism of action of DTX, which targets microtubules, we showed that Nufs-DTX exhibited similar effects in proliferation and clonogenic assays using A549 cells. Interestingly, we observed that Nufs-DTX had a greater in vivo tumor growth delay effect on an A549 xenograft model than Taxotere™, which was in agreement with the improved drug accumulation in tumors according to the biodistribution result, and was caused by the enhanced permeability and retention (EPR) effect. Although both Nufs-DTX and Taxotere™ showed negative results for our administration dose in the hematologic toxicity test, Nufs-DTX showed much less toxicity than Taxotere™ in edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2), maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs.

Enhancement of radiotherapeutic efficacy by paclitaxel-loaded pH-sensitive block copolymer micelles

Radiotherapy (RT) is a major modality for cancer treatment, but its efficacy is often compromised by the resistance caused by tumor-specific microenvironment including acidosis and hypoxia. For an effective RT, concurrent administration of radiosensitizer with RT has been emphasized. However, most anticancer agents enhancing radiotherapeutic efficacy have obstacles such as poor solubility and severe toxicity. Paclitaxel (PTX), a well-known radiosensitizer, is insoluble in water and needs toxic solvent like Cremophor EL. Nanomaterials in drug delivery systems have been utilized for improving the drawbacks of anticancer drugs. Solubilization, tumor accumulation, and toxicity attenuation of drug by nanomaterials are suitable for enhancement of radiotherapeutic efficacy. In this study, PTX was incorporated into pH-sensitive block copolymermicelle (psm-PTX), polyethylene glycol-graft-poly(β-amino ester), and preclinically evaluated for its effect on RT. The size of psm-PTX was 125.7 ± 4.4nm at pH 7.4. psm-PTX released PTX rapidly in the acidic condition (pH 6.5), while it was reasonably stable in the physiologic condition (pH 7.4). The clonogenic assay showed that psm-PTX greatly sensitized human non-small-cell lung cancer A549 cells to radiation. In the xenograft tumor model, the combination of psm-PTX and radiation significantly delayed the tumor growth. These results demonstrated the feasibility of psm-PTX to enhance the chemoradiotherapeutic efficacy.

How to reduce lethal infectious complications in ABO-incompatible kidney transplantation.

BACKGROUND ABO-incompatible organ transplants are good options for expanding the living donor pool; however, the necessary pre-conditioning to remove ABO antibodies before surgery can evoke critical infectious complications after surgery. METHODS Between February 2009 and July 2013, we performed ABO-incompatible kidney transplantation on 182 patients. We analyzed the first 85 patients for post-operative infectious complications in a cross-sectional cohort of patients (group 1, n = 85) who had received an ABO-incompatible kidney transplant and, in light of the results, amended the pre-conditioning (lower dose of rituximab, selective use of calcineurin inhibitors, anti-metabolite reduction, and prophylactic strategy) given to a prospective cohort (group 2, n = 97). RESULTS The characteristics of the two groups did not differ significantly. Infectious complications decreased significantly in group 2, including cytomegalovirus (anti-genemia 64.7% vs 27.8%, P < .001) and BK viremia (35.2% vs 18.6%, P = .008). The acute rejection rate and death-censored graft survival were similar in both groups. Notably, with the modified protocol, there were no deaths (8.2% vs 0.0%, P = .03). CONCLUSIONS Pre-conditioning for ABO-incompatible kidney transplantation is a prerequisite for successful outcome; its drawbacks can be limited with the use of a modified immunosuppressive strategy. If immunosuppression is modified according to host conditions, ABO-incompatible kidney transplantation can be performed safely with a successful graft outcome.

A cisplatin‑incorporated liposome that targets the epidermal growth factor receptor enhances radiotherapeutic efficacy without nephrotoxicity

Radiotherapy (RT) is one of the major modalities for non‑small cell lung cancer (NSCLC), but its efficacy is often compromised by cellular resistance caused by various mechanisms including the overexpression of epidermal growth factor receptor (EGFR). Although cis‑diamminedichloroplatinum(Ⅱ) (cisplatin, CDDP) has been well characterized as an effective radiosensitizer, its clinical application is limited by its severe nephrotoxic effects. In our current study, we developed a CDDP‑incorporated liposome (LP) conjugated with EGFR antibodies (EGFR:LP‑CDDP) and evaluated its potential to radiosensitize EGFR‑overexpressing cells without exerting nephrotoxic effects. EGFR:LP‑CDDP showed higher cytotoxicity than non‑targeting liposomal CDDP (LP‑CDDP) in the cells expressing EGFR in vitro. In an A549 cell‑derived xenograft tumor mouse model, increased delays in tumor growth were observed in the mice treated with a combination of EGFR:LP‑CDDP and radiation. Notably, the EGFR:LP‑CDDP‑treated animals showed no differences in body weight loss, survival rates of nephrotoxicity compared with untreated control mice. In contrast, the use of CDDP caused lower body weights and poorer survival outcomes accompanied by a significant level of nephrotoxicity [e.g., decreased kidney weight, increased blood urea nitrogen (BUN) and creatinine, and pathological change]. These findings suggest the feasibility of using EGFR:LP‑CDDP to radiosensitize cells in a targeted manner without inducing nephrotoxic effects. This compound may therefore have clinical potential as part of a tailored chemoradiotherapy strategy.

Outcomes of En Bloc Kidney Transplantation From Pediatric Donors: A Single-Center Experience

BACKGROUND To overcome a shortage of donors, cadaveric pediatric en bloc kidneys can be used to expand the donor pool. Recent evidence shows that en bloc kidney transplantation (EBKT) has better outcomes than standard-criteria deceased adult donor kidney transplantation. We reviewed our experiences of EBKT and their outcomes. METHODS From September 1996 to January 2016, 15 EBKTs were performed in Asan Medical Center. The characteristics of donors and recipients were analyzed. Graft survival was analyzed by means of serum creatinine levels. RESULTS Nine male and 6 female donors were used. The mean age and body weight of donors was 2.79 years (range, 0.25-14) and 13.14 kg (range, 5.5-35). The mean weight of en bloc kidneys was 117.43 g (range, 36-146). Recipient median age was 39.13 years and body weight was 49.47 kg. Ureteral anastomosis was performed by means of side-to-side anastomosis and then bladder anastomosis in 9 patients and by bladder patch anastomosis in 4 patients. Serum creatinine levels at discharge and latest follow-up were 0.97 mg/dL (range, 0.7-1.54) and 0.89 mg/dL (range, 0.44-2.58). Delayed graft function developed in 3 patients and clinical rejection developed in 2 patients. We performed graftectomy on post-operative day 1 because of graft thrombosis. The rest maintained their graft function well. Graft survival was comparable with that of kidney transplantation from standard donors. CONCLUSIONS EBKT showed excellent graft function and outcomes at our center. As an approach to expand the donor pool and improve graft utilization, EBKT is acceptable and should be more widely used.

Enhanced detection of single-cell-secreted proteins using a fluorescent immunoassay on the protein-G-terminated glass substrate [Corrigendum]

[This corrects the article on p. 7197 in vol. 10, PMID: 26648723.].