Joo Ho Kim

Photosensitizing hollow nanocapsules for combination cancer therapy

The social and economic burden of cancer demands a spectrum of therapeutic methodologies. Current options include surgery, chemotherapy, radiotherapy, hyperthermia, and photodynamic therapy (PDT). Only rarely, however, is a single methodology sufficient to overcome cancer. This requirement has inspired combination regimens that overcome the additive, synergistic, and complementary interactions between treatments. An important advance in combination cancer therapy was achieved with the fabrication of multifunctional nanomaterials, including polymeric micelles and nanoparticles (NPs), which may be used to simultaneously perform more than one therapy. Polymeric multilayer capsules present several advantages in combination cancer therapy, including a relatively high capacity for the active substance and versatility in fabrication of the capsule shell. The hollow capsules are assembled in a layer-by-layer (LbL) process onto a sacrificial template followed by dissolution of the template. Hollow polymeric capsules can be fabricated by using templates that vary in size from a few nanometers to hundreds of micrometers, and their chemical and mechanical properties can be precisely tailored by modulating the thickness and composition of the shell. Polymeric multilayer capsules attract interest in various fields of research, and most recently for their high loading capacity as vehicles in drug delivery systems (DDSs). Based on this background, we developed a new type of hollow nanocapsule (NC) for use in combining PDT with chemotherapy. To produce the photosensitizer, we synthesized a negatively charged dendritic porphyrin (DP) that was shown to be effective photosensitizer for PDT, and combined it as a bilayer component with poly(allylamine hydrochloride) (PAH) to fabricate hollow NCs. In general, photosensitizers have large p-conjugation domains for high quantum yields and effective energy absorption. Therefore, many photosensitizers can easily form aggregates in aqueous media because of their abilities to form p–p interactions and their hydrophobic characteristics, which provide a self-quenching effect of the excited state. Unlike conventional photosensitizers, DP has large dendritic wedges that effectively prevent self-quenching phenomena. Moreover, when the DP forms self-assembled nanostructures such as polymeric micelles, large numbers of DPs can effectively generate a high concentration of singlet oxygen at local sites in order to overcome the threshold concentration for oxidative damage. The (PAH/DP)n multilayer nanocapsules were filled with doxorubicin (DOX), a model anticancer drug, in order to implement chemotherapy. While most NC shells used in DDS are prepared from linear polyelectrolytes that lack any function other than drug container, our system employs DP as not only a polyelectrolyte for the formation of NC shells but also as photosensitizing units for photodynamic therapy. Figure 1 shows the preparation of hollow NCs by alternating deposition of PAH and DP onto a negatively charged polystyrene (PS) NP and the subsequent removal of the template PS NP. The average molecular weight of PS was determined to be 70 kDa by GPC analysis. It has been reported that dissolved PS (Mw 10 Da) can diffuse through the multilayer shells when they were extracted with organic solvents such as chloroform or tetrahydrofuran. The DP used in this study bears 32 carboxylate groups on its periphery and a negative zeta potential ( 31.0 mV) at pH 7.4. We expected that multilayer shells would be formed by this LbL deposition technique based on the electrostatic interaction between positively charged PAH and negatively charged DP. The stepwise formation of multilayer shells onto PS NPs was monitored by observing zeta potential changes of particles after each deposition step (Figure 2a). The bare PS NPs have a zeta potential of approximately 55 mV. The PS NPs coated with layers of PAH and DP showed discrete zeta potentials that alternate between positive or negative, depending on the outer layer type. This observation showed that the multilayer surface was charge-overcompensated in each adsorption step, which facilitated adsorption of the next oppositely charged capsule shell layer. Owing to the strong UV/Vis absorbance and fluorescence (FL) emission of DP, multilayer formation could be monitored by changes in UV/Vis absorbance and FL emission from the multilayer-coated PS particles (NCn PS; n = numbers of LbL bilayer, n = 1–3). As shown in Figure 2b, the UV/Vis absorbance and FL emission increased with the number of bilayers. Quantities of DP deposited in NCs were determined to be (106.2 0.4), (212.6 0.4), and (366.1 [*] K. J. Son, Y. Lee, Prof. W.-G. Koh Department of Chemical and Biomolecular Engineering Yonsei University 50 Yonsei-ro, Seodaemoon-Gu, Seoul 120-749 (Korea) E-mail: wongun@yonsei.ac.kr H.-J. Yoon, J.-H. Kim, Prof. W.-D. Jang Department of Chemistry, Yonsei University 50 Yonsei-ro,Seodaemoon-Gu, Seoul 120-749 (Korea) E-mail: wdjang@yonsei.ac.kr [] These authors contributed equally to this work.

Fabrication of multifunctional layer-by-layer nanocapsules toward the design of theragnostic nanoplatform.

Self-assembled polymeric nanocapsules (NCs) that incorporate dendrimer porphyrin (DP) in the shells and superparamagnetic iron oxide nanoparticles (SPIONs) in the cores are fabricated to create a theragnostic platform for the application in photodynamic therapy (PDT) and magnetic resonance imaging (MRI). SPIONs-embedded polystyrene NPs (SPIONs@PS) are used as a template to build up multilayered NCs. The formation of PAH/DP multilayer on the SPIONs@PS is monitored by zeta-pential and fluorescence emission measurement, because the porphyrin unit in the core of DP has strong red fluorescence emission. NCs have strong enough magnetic property (>20 emu/g) for MRI application with typical superparamagnetic behavior, where the linear correlation of R2 and Fe concentration at diluted conditions led to corresponding T2 relaxivity coefficient (r2) value of 93.5 mM(-1) s(-1). Cell viability study upon light irradiation reveals that NCs can successfully work in photosensitizer formulation for PDT.

Dual stimuli-responsive dendritic-linear block copolymers

Dendritic-linear block copolymers that have pH responsive poly(benzyl ether) dendrons and temperature responsive PiPrOx chains have been designed by copper-mediated click reactions. These copolymers exhibit sharp thermal transitions with a wide range of pH-dependent thermal transition temperatures.

Supramolecular Coordination Polymer Formed from Artificial Light-Harvesting Dendrimer

We report the formation of supramolecular coordination polymers formed from multiporphyrin dendrimers (PZnPM; M = FB or Cu), composed of the focal freebase porphyrin (PFB) or cupper porphyrin (PCu) with eight zinc porphyrin (PZn) wings, and multipyridyl porphyrins (PyPM; M = FB or Cu), PFB or PCu with eight pyridyl groups, through multiple axial coordination interactions of pyridyl groups to PZns. UV-vis absorption spectra were recorded upon titration of PyPFB to PZnPFB. Differential spectra, obtained by subtracting the absorption of PZnPFB without guest addition as well as the absorption of PyPFB, exhibited clear isosbestic points with saturation binding at 1 equiv addition of PyPFB to PZnPFB. Jobs plot analysis also indicated 1:1 stoichiometry for the saturation binding. The apparent association constant between PZnPFB and PyPFB (2.91 × 10(6) M(-1)), estimated by isothermal titration calorimetry, was high enough for fibrous assemblies to form at micromolar concentrations. The formation of a fibrous assembly from PZnPFB and PyPFB was visualized by atomic force microscopy and transmission electron microscopy (TEM). When a 1:1 mixture solution of PZnPFB and PyPFB (20 μM) in toluene was cast onto mica, fibrous assemblies with regular height (ca. 2 nm) were observed. TEM images obtained from 1:1 mixture solution of PZnPFB and PyPFB (0.1 wt %) in toluene clearly showed the formation of nanofibers with a regular diameter of ca. 6 nm. Fluorescence emission measurement of PZnPM indicated efficient intramolecular energy transfer from PZn to the focal PFB or PCu. By the formation of supramolecular coordination polymers, the intramolecular energy transfer changed to intermolecular energy transfer from PZnPM to PyPM. When the nonfluorescent PyPCu was titrated to fluorescent PZnPFB, fluorescence emission from the focal PFB was gradually decreased. By the titration of fluorescent PyPFB to nonfluorescent PZnPCu, fluorescence emission from PFB in PyPFB was gradually increased due to the efficient energy transfer from PZn wings in PZnPCu to PyPFB.

Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia

ObjectivesTo evaluate the necessity of adaptive planning in helical tomotherapy (TOMO) for head and neck cancer in terms of dosimetric influence on the parotid gland. MethodsThirty-one patients underwent curative TOMO for head and neck cancer from April 2006 to April 2007. For each patient, neck diameter was monitored together with body weight at first cervical spine level through mega-voltage computed tomography during the TOMO course. Ten of 31 patients, with significant weight loss (>5%) and/or neck diameter decrease (>10%), were selected for dosimetric analysis, and parotid dose was recalculated at the fourth and last week of TOMO. Xerostomia was estimated by Radiation Therapy Oncology Group criteria. ResultsThe median dose was 69.96 Gy (range, 54 to 69.96 Gy) and there was no grade 3 or greater complication. Ten patients with significant neck diameter decrease and/or weight loss showed frequent grade 2 acute xerostomia (P=0.02). The volume percentage of daily fractional dose over 0.75 Gy for the parotid gland (V0.75 Gy) increased by 23.6% at the end of TOMO. ConclusionsFor patients with significant anatomic contour change; neck diameter decrease (>10%) or weight loss (>5%), adaptive planning using mega-voltage computed tomography can identify dosimetric changes and reduce deleterious side effects such as xerostomia.

Thermoresponsive Polymer and Fluorescent Dye Hybrids for Tunable Multicolor Emission

Fully reversible emission color change is achieved by blending a thermoresponsive polymer with dye hybrids. The emission color can be tuned by changing the mixing ratio of each polymer-dye hybrid.

Selection of the Optimal Radiotherapy Technique for Locally Advanced Hepatocellular Carcinoma

OBJECTIVEnVarious techniques are available for radiotherapy of hepatocellular carcinoma, including three-dimensional conformal radiotherapy, linac-based intensity-modulated radiotherapy and helical tomotherapy. The purpose of this study was to determine the optimal radiotherapy technique for hepatocellular carcinoma.nnnMETHODSnBetween 2006 and 2007, 12 patients underwent helical tomotherapy for locally advanced hepatocellular carcinoma. Helical tomotherapy computerized radiotherapy planning was compared with the best computerized radiotherapy planning for three-dimensional conformal radiotherapy and linac-based intensity-modulated radiotherapy for the delivery of 60 Gy in 30 fractions. Tumor coverage was assessed by conformity index, radical dose homogeneity index and moderated dose homogeneity index. Computerized radiotherapy planning was also compared according to the tumor location.nnnRESULTSnTumor coverage was shown to be significantly superior with helical tomotherapy as assessed by conformity index and moderated dose homogeneity index (P= 0.002 and 0.03, respectively). Helical tomotherapy showed significantly lower irradiated liver volume at 40, 50 and 60 Gy (V40, V50 and V60, P= 0.04, 0.03 and 0.01, respectively). On the contrary, the dose-volume of three-dimensional conformal radiotherapy at V20 was significantly smaller than those of linac-based intensity-modulated radiotherapy and helical tomotherapy in the remaining liver (P= 0.03). Linac-based intensity-modulated radiotherapy showed better sparing of the stomach compared with helical tomotherapy in the case of separated lesions in both lobes (12.3 vs. 24.6 Gy). Helical tomotherapy showed the high dose-volume exposure to the left kidney due to helical delivery in the right lobe lesion.nnnCONCLUSIONSnHelical tomotherapy achieved the best tumor coverage of the remaining normal liver. However, helical tomotherapy showed much exposure to the remaining liver at the lower dose region and left kidney.

Dendrimer porphyrin-terminated polyelectrolyte multilayer micropatterns for a protein microarray with enhanced sensitivity

Through a combination of layer-by-layer (LbL) self-assembly (SA) and lift-off methods, a dendrimer-coated polyelectrolyte multilayer micropattern was prepared for protein microarrays. A silicon substrate was patterned with a photoresist thin film using conventional photolithography, and then poly(ethyleneimine) (PEI) and poly(sodium 4-styrenesulfonate) (PSS) were alternatively deposited onto the substrate surface using spin-assisted self-assembly. A well-defined multilayer microarray was produced by subsequent removal of the photoresist template by a lift-off process. Dendrimer porphyrin (DP) was successively immobilized onto the PEI-terminated micropatterns via electrostatic interactions between the negatively-charged DPs and positively-charged PEI segments. Because of strong fluorescence from focal porphyrins, the homogeneous covering of DPs onto the multilayer micropatterns was easily confirmed using fluorescence microscopy. Atomic force microscopy (AFM) also showed morphological change of micropatterned surfaces by DP immobilization. Based on these results, IgG was immobilized on the DP-coated protein microarrays, and immunoassays were performed to demonstrate that the DP-coated microarrays yielded a higher fluorescence signal and were more sensitive than the control microarrays that were coated with linear PAA polymer instead of DP due to the multiple functional groups present on the DP-coated arrays and their increased surface area relative to control microarrays.

Dosimetric Comparisons of Three-dimensional Conformal Radiotherapy, Intensity-Modulated Radiotherapy, and Helical Tomotherapy in Whole Abdominopelvic Radiotherapy for Gynecologic Malignancy

Objectives The goal of this study was to dosimetrically compare 3-dimensional radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (TOMO) plans for whole abdominopelvic radiotherapy (WART) in patients with gynecologic cancer. Methods Ten patients were selected for WART planning. Doses were prescribed to planning target volumes (PTVs) as the followings: 30 Gy to PTV-whole abdominopelvis (PTV-WA), 40 Gy to PTV-para-aortic lymph node (PTV-PALN), 44 Gy to PTV-pelvis, and 50 Gy to gross target volume (GTV) in 20 fractions. Dose to whole liver, both kidneys, and spinal cord were constrained below each tissue tolerance, and bone marrow (BM)-sparing technique was adopted in IMRT and TOMO. Dosimetric parameters and treatment times were compared among plans. Results Calculated doses in TOMO came most closely to the prescribed dose for coverage of PTV-WA, PTV-PALN, PTV-pelvis, and GTV compared to 3DCRT, and IMRT. In normal organs, TOMO had significantly better dosimetric profiles compared to IMRT and 3DCRT. TOMO significantly reduced V20Gy, and mean dose of whole liver, both kidneys, and spinal cord. The use of BM-sparing technique (BMS) did not impair coverage of target volume in IMRT and TOMO. While IMRT showed no differences of irradiated BM dose using BMS, TOMO with BMS reduced half V20Gy of BM compared to TOMO without BMS. Conclusions TOMO showed dosimetric superiority in target coverage, sparing BM, and other normal organs compared to 3DCRT and IMRT. Clinical experiences will be needed for evaluation of feasibility of WART using TOMO in patients with gynecologic cancer.

Is helical tomotherapy accurate and safe enough for spine stereotactic body radiotherapy

PurposeWe assessed the accuracy and safety of spine stereotactic body radiation therapy (SBRT) using helical tomotherapy (HT) via evaluating intrafractional patient movement.MethodsFrom July 2009 to April 2011, 22 patients with spine lesions received SBRT using HT, with a total of 61 fractions. To evaluate intrafractional movement, we compared post-treatment megavoltage CT scans with planning CT images and obtained translational [lateral (X), craniocaudal (Y), anterioposterior (Z)] offsets and total displacements (R). We analyzed the correlation of intrafractional motion with patient and treatment characteristics. We also analyzed dosimetric change to the target and spinal cord, resulting from intrafractional movement, in the three patients that showed the greatest R values.ResultsIntrafractional movements were 0.7xa0±xa00.6xa0mm (X), 1.1xa0±xa00.7xa0mm (Y), 0.9xa0±xa00.6xa0mm (Z), and 1.8xa0±xa00.6xa0mm (R). This movement did not correlate with age, pain score, treatment time, or treatment site. Only patients with lower BMIs have a tendency to move more during treatment. Patient immobilization using wrapping form (thermoplastic mask and BodyFIX® system) resulted in less lateral movement and total displacement than others (0.498xa0±xa00.409 vs. 1.138xa0±xa00.637xa0mm, Pxa0<xa00.001 for X; and 1.638xa0±xa00.691 vs. 1.976xa0±xa00.495xa0mm, Pxa0=xa00.032 for R). However, this intrafractional motion did not affect the dose delivery to the target and spinal cord.ConclusionSBRT using HT can be a safe treatment modality for spine metastasis with enhanced targeting accuracy.