Jung-Kyo Cho

Thermosensitive/magnetic poly(organophosphazene) hydrogel as a long-term magnetic resonance contrast platform

A thermosensitive/magnetic poly(organophosphazene) hydrogel (a magnetic hydrogel) was designed and synthesized for long-term magnetic resonance (MR) imaging. To turn a thermosensitive poly(organophosphazene) hydrogel (an original hydrogel) into a long-term MR contrast platform, cobalt ferrite (CoFe(2)O(4)) nanoparticles, which have hydrophobic surfaces, were bound to the original hydrogel via interactions between the hydrophobic surfaces of the nanoparticles and the (L)-isoleucine ethyl esters of the polymer. The magnetic hydrogel showed extremely low cytotoxicity and adequate magnetic properties for use in long-term MR imaging, in addition to possessing the same properties of the original hydrogel, such as viscosity, thermosensitivity, biodegradability, biocompatibility, a reversible sol-to-gel phase transition near body temperature, and injectability. The magnetic hydrogel was injected into a rat brain using stereotactic surgery. After the injection, the applicable potentiality as a long-term MR contrast platform was successfully estimated over 4-5 weeks. Consequently, it was shown that a magnetic hydrogel as a long-term MR contrast platform has the potential to be applied in a long-term theranostic hydrogel system. Furthermore, it is expected that this platform can be useful in the clinical field of incurable diseases due to either surgical difficulties or lethality, such as with brain tumors, when the platform is combined with therapeutic drugs for long-term MR theragnosis in further studies.

Long-term theranostic hydrogel system for solid tumors.

The long-term theranostic hydrogel system for solid tumors was prepared via simple physical mixing, which consisted of three major parts: the thermosensitive/biodegradable poly(organophosphazene) hydrogel, PEGylated cobalt ferrite nanoparticles, and paclitaxel (PTX). The PEGylated cobalt ferrite nanoparticles showed extremely low cytotoxicity due to the surface modification using PEG chains. The long-term theranostic hydrogel system showed adequate properties to be used for long-term MR theragnosis. In particular, the theranostic hydrogel gradually degraded over 28 days, and the PTX was sustainedly released out from the theranostic hydrogel over the same period in vitro. Furthermore, the in vivo efficacy of long-term MR theragnosis using the theranostic hydrogel system was estimated successfully over 3 weeks by using high field (4.7 T) animal MRI and solid tumor-bearing mice. Based on our results, we expect that this system can supply multiple data regarding a) the progress of therapy and b) the treatment processes via one- or two-time i.t. administration for cases in which surgical approaches are difficult to apply. Meanwhile, cancer patients can be free from the pain of multiple surgical treatments and have the advantage of therapy through a simple i.t. administration.

Injectable and Biodegradable Poly(organophosphazene) Gel Containing Silibinin: Its Physicochemical Properties and Anticancer Activity

The biodegradable poly(organophosphazene) hydrogels were developed as a locally injectable drug carrier for a hydrophobic silibinin to overcome its limited bioavailability. The aqueous solution of poly(organophosphazene) enhanced the solubility of silibinin up to 2000 times compared with that of phosphate buffered saline (0.0415 vs. 84.55 mg/mL). Both aqueous polymer solutions with and without silibinin showed a sol-gel transition as a function of temperature. A faster in vitro degradation rate of the gel and drug release rate from the gel at pH 6.8 than those at pH 7.4 were observed when the degradation and release study on hydrogels were conducted at 37 °C. Silibinin was sustainedly released from the hydrogel mainly by a diffusion-controlled mechanism. The silibinin released from the hydrogel was shown to be effective considering the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the HT-29 xenografted mice model, the intratumorally injected hydrogel containing silibinin exhibited a good antitumor effect in comparison with the control groups. The Western blotting indicated that one of the reasons for the enhanced antitumor effect of the hydrogel system was the sustained antiangiogenic effect of silibinin. The poly(organophosphazene) gels are expected to be an effective candidate of the locally injectable drug carrier for silibinin.

Injectable delivery system of 2-methoxyestradiol for breast cancer therapy using biodegradable thermosensitive poly(organophosphazene) hydrogel

2-Methoxyestradiol (2-ME) has been reported to have antiangiogenic and antitumor activity. Its biomedical application is limited due to its poor water solubility resulting in its low bioavailability. Poly(organophosphazenes) containing l-isoleucine ethyl ester, ethyl-2-(O-glycyl)lactate, and α-amino-ω-methoxy-poly(ethylene glycol) 550 were synthesized having MW of 35–38 kDa and polydispersity index of 2.38–2.73. Using a viscometer, the thermosensitivity useful for locally injectable drug delivery was verified. The aqueous polymer solution showed a sol state at a low temperature and transformed to a gel state at body temperature. The polymer solution (10 wt%) enhanced the solubility of 2-ME by about 104 times compared to that of phosphate buffered saline. 2-ME was released from the hydrogel mainly by diffusion, hydrophobic interaction, and surface erosion of the matrix. This release profile could be confirmed through an in vitro release test as a function of polymers and the concentration of 2-ME in hydrogels. By monitoring tumor volume and CD31 immunohistochemical staining in mouse orthotopic breast tumor (MDA-MB-231) model, it was found that the hydrogel containing a relatively low concentration (15 mg/kg) of 2-ME showed the improved antitumor and antiangiogenic activity relative to the original formulation. This research suggests that the developed formulation of poly(organophosphazenes) may have injectable carrier potentials for 2-ME and other lipophilic drugs.

Injectable poly(organophosphazene)-camptothecin conjugate hydrogels: synthesis, characterization, and antitumor activities.

The objective of this study is to develop an effective polymer therapeutics involving camptothecin (CPT) with enhanced efficacy and lessened systemic side-toxicity for cancer treatment. Polymer-CPT conjugates (PCCs), which consisted of CPT-20-glycinate and poly(organophosphazene) bearing carboxylic acid, were synthesized, characterized for physicochemical properties, in vitro degradation and CPT release behaviors from the PCC, and evaluated their anticancer activity. The aqueous solutions of all these PCCs showed a thermo-responsive sol-gel transition behavior for injectable application near room temperature. The CPT incorporated into the hydrogel was proven to be stable in vitro over 15 days. The in vitro cytotoxicity of the PCC was verified to be effective against four kinds of human cancer cell lines. The in vivo anticancer activity study with HT-29 colon cancer cell xenografted mice showed that the intratumorally injected PCC hydrogel inhibited the tumor growth more effectively relative to CPT alone (-29% vs. 130% in tumor size).

Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8 wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3 mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p < 0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.

Injectable poly(organophosphazene) hydrogel system for effective paclitaxel and doxorubicin combination therapy

Abstract Combination therapy is an important option for gastric cancer which is the second leading cause of cancer-related death worldwide. The administration schedule of cell cycle-specific drugs, such as doxorubicin (DOX) and paclitaxel (PTX), is important for therapeutic efficacy. However, to control the schedule is clinically inconvenient. Additionally, in vitro cytotoxicity tests against human gastric cancer cells (SNU-601) showed that the combination indices (CIs) of DOX and PTX were 1.43 (α = 0) and 1.90 (α = 1), respectively, indicating that the DOX and PTX interaction was antagonistic. Thus, based on the finding that the release rate of drugs from poly(organophosphazene) (PPZ) hydrogel is dependent on the hydrophobicity of the drugs, we used injectable PPZ hydrogel in combination therapy. In vivo anticancer activity test in human gastric cancer cell-xenografted mice showed that intratumoral injection with aqueous PPZ solution, containing DOX (15 mg/kg) and PTX (30 mg/kg), resulted in the highest tumor inhibition and safety (no mortality for approximately 3 months) in the experimental groups. Consequently, PPZ hydrogel is expected to be a promising drug delivery system for cell cycle-specific drugs, facilitating the control of their administration schedule for effective combination therapy.

Improvement of anti-cancer drug efficacy via thermosensitive hydrogel in peritoneal carcinomatosis in gastric cancer

Peritoneal carcinomatosis (PC) of gastric origin has a poor prognosis with short survival due to lack of effective therapeutic modalities. Here, we evaluated the therapeutic efficacy of an injectable thermosensitive poly (organophosphazene) (PPZ) hydrogel with docetaxel (DTX-gel) to develop an effective therapeutic agent for patient with PC. Three days after inoculation of highly metastatic 44As3Luc cells into peritoneal cavity, the mice were intravenously or intraperitoneally administered with docetaxel alone (DTX-sol IV or IP), and intraperitoneally injected with DTX-gel. The anti-tumor activity was monitored by bioluminescence live imaging system. Compared to DTX-sol IV or IP, the tumor growth was significantly reduced in the DTX-gel treated mice (p<0.0001, p=0.0001). Furthermore, the survival rate was significantly increased in the DTX-gel treated mice compared to DTX-sol IV or IP treated mice (p<0.0001, p=0.0068). Our results demonstrated that DTX-gel suppresses peritoneal metastasis by continuing release of chemotherapy agent, which leads to increase the survival rate in a PC model. Therefore, biodegradable thermosensitive hydrogel with docetaxel system can be a good anti-cancer agent for PC.