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One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid- co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phantoms, and the constructs were treated daily for 14 days with ultrasound at 2.2 W/cm for 10 min. The 2D distribution of fluorescein within the phantoms was quantified using fluorescence imaging. Implants receiving ultrasound irradiation showed a 1.7-5.6 fold increase ( p < 0.05) in fluorescence intensity and penetration distance, with the maximum increase observed 5 days post-implantation. However, this evidence was not seen when the same experiment was also carried out in phosphate buffer saline (pH 7.4). Results suggest an active role of ultrasound in local molecular transport in the phantom. An increase of fluorescein release and penetration depth in phantoms can be accomplished through brief application of ultrasound. This simple technique offers an opportunity to eventually enhance the therapeutic efficacy and broaden the application of local drug delivery systems. [ABSTRACT FROM AUTHOR]

Polymeric micelles of poly(ethylene glycol)- block-poly(ɛ-caprolactone) bearing glucose analog encapsulated with superparamagnetic iron oxide nanoparticles (Glu-SPIO micelles) were synthesized as an MRI contrast agent to target cancer cells based on high-glucose metabolism. Compared to SPIO micelles (non-targeting SPIO micelles), Glu-SPIO micelles demonstrated higher toxicity to human prostate cancer cell lines (PC-3) at high concentration. Atomic absorption spectroscopy was used to determine the amount of iron in cells. It was found that the iron in cancer cells treated by Glu-SPIO micelles were 27-fold higher than cancer cells treated by SPIO micelles at the iron concentration of 25 ppm and fivefold at the iron concentration of 100 ppm. To implement Glu-SPIO micelles as a MR contrast agent, the 3-T clinical MRI was applied to determine transverse relaxivities ( r *) and relaxation rate (1/ T *) values. In vitro MRI showed different MRI signal from cancer cells after cellular uptake of SPIO micelles and Glu-SPIO micelles. Glu-SPIO micelles was highly sensitive with the r * in agarose gel at 155 mM s. Moreover, the higher 1/ T * value was found for cancer cells treated with Glu-SPIO micelles. These results supported that glucose ligand increased the cellular uptake of micelles by PC-3 cells with over-expressing glucose transporter on the cell membrane. Thus, glucose can be used as a small molecule ligand for targeting prostate cancer cells overexpressing glucose transporter. [ABSTRACT FROM AUTHOR]

The objective of this work was to develop self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system for liver cancer chemotherapy and studied the release profiles of doxorubicin (Dox) from different depot formulations. Tri-block copolymers of poly( ε-caprolactone), poly(D,L-lactide) and poly(ethylene glycol) named PLECs were successfully used as a biodegradable material to encapsulate Dox as the injectable local drug delivery system. Depot formation and encapsulation efficiency of these depots were evaluated. Results show that depots could be formed and encapsulate Dox with high drug loading content. For the release study, drug loading content (10, 15 and 20% w/w) and polymer concentration (25, 30, and 35% w/v) were varied. It could be observed that the burst release occurred within 1-2 days and this burst release could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. The degradation at the surface and cross-section of the depots were examined by Scanning Electron Microscope (SEM). In addition, cytotoxicity of Dox-loaded depots and blank depots were tested against human liver cancer cell lines (HepG2). Dox released from depots significantly exhibited potent cytotoxic effect against HepG2 cell line compared to that of blank depots. Results from this study reveals an important insight in the development of injectable drug delivery system for liver cancer chemotherapy. Graphical Abstract: Schematic diagram of self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system and in vitro characterizations. (a) Dox-loaded PLEC depots could be formed with more than 90% of sustained-release Dox at 25% polymer concentration and 20% Dox-loading content. The burst release occurred within 1-2 days and could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. (b) Dox released from depots significantly exhibited potent cytotoxic effect against human liver cancer cell lines (HepG2 cell line) compared to that of blank depots. (c) Dox-loaded depots showed bulk erosion with hollow core at day 60. [ABSTRACT FROM AUTHOR]

Layer-by-layer (LbL) dip coating, accompanying with the use of micelle structure, allows hydrophobic molecules to be coated on medical devices' surface via hydrogen bonding interaction. In addition, micelle structure also allows control release of encapsulated compound. In this research, we investigated methods to coat and maximize the amount of chlorhexidine (CHX) on silicone surface through LbL dip coating method utilizing hydrogen bonding interaction between PEG on micelle corona and PAA. The number of coated cycles was varied in the process and 90 coating cycles provided the maximum amount of CHX loaded onto the surface. In addition, pre-coating the surface with PAA enhanced the amount of coated CHX by 20%. Scanning electron microscope (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) were used to validate and characterize the coating. For control release aspect, the coated film tended to disrupt at physiological condition; hence chemical crosslinking was performed to minimize the disruption and maximize the release time. Chemical crosslinking at pH 2.5 and 4.5 were performed in the process. It was found that chemical crosslinking could help extend the release period up to 18 days. This was significantly longer when compared to the non-crosslinking silicone tube that could only prolong the release for 5 days. In addition, chemical crosslinking at pH 2.5 gave higher and better initial burst release, release period and antimicrobial properties than that of pH 4.5 or the normal used pH for chemical crosslinking process. [ABSTRACT FROM AUTHOR]

Purpose: SN-38, a potent chemotherapeutic drug, has not been used clinically because of its severe side effects and poor solubility. In this work, we aimed to evaluate the effect of dose and multiple injections of SN-38-loaded polymeric depots on antitumor efficacy and toxicity in vivo. Methods: Preparation and characterization of SN-38-loaded depots were performed and evaluated in vitro using human glioblastoma cell line, U-87MG. Antitumor efficacy with different depot administrations including dose, position of depot injection and number of injections were evaluated in tumor model in nude mice. Results: Depots encapsulated SN-38 with high encapsulation efficiency (~98.3%). High amount of SN-38 (3.0 ± 0.1 mg) was prolonged and controlled release over time and showed anticancer activity against U-87MG cell line in vitro. For one course administration, depots exhibited better antitumor efficacy and reduced toxicity compared to free SN-38. Elevated doses and multiple injections of SN-38-loaded depots and free SN-38 provided greater tumor growth inhibition and animal survival. All animals received SN-38-loaded depots were well tolerated and survived while most of those received free SN-38 died at day 30. Free SN-38 showed severe toxic effect compared to minimal toxicity from SN-38-loaded depots which was due to lower SN-38 level in systemic circulation. Fluorescence imaging and histopathology confirmed that SN-38 released from depots was detected throughout tumors 35 days post administration. Conclusions: SN-38-loaded depots were proved as a promising new treatment for highly invasive glioblastoma multiforme with low acute toxicity due to controlled release of SN-38. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are the most common type of hospital-acquired infection which cause significant morbidity and mortality. Antibacterial urinary devices to prevent UTIs are in great demand, while the problem of releasing antibacterials is still limited by duration of antibacterial release and hinders their clinical applications. This study investigated a new approach to sustain release of chlorhexidine (CHX) from urinary devices by coating of chlorhexidine-loaded nanospheres (CHX-NPs) on the surface. CHX-NPs were prepared by high-pressure emulsification-solvent evaporation technique that provided the size of nanospheres at 198.8 nm and the drug loading content at 5.6 %. These nanospheres were spray-coated on silicone surface with reproducible and predictable amount of CHX. Release studies conducted in artificial urine to mimic in vivo condition showed that suitable dose of CHX was released in a sustained manner within a couple of weeks. Additionally, CHX-NPs showed antibacterial activity against common bacteria causing UTIs up to 15 days, which is threefold longer than that of physical mixing between CHX and polymer. Results from this study suggest possible applications of CHX-NPs in coating the surface of ureteral-relating devices for sustained antibacterial release. [ABSTRACT FROM AUTHOR]

Copolymers of (D,L-lactide-random-ε-caprolactone)-block-poly(ethylene glycol)-block-(D,L-lactide-random-ε-caprolactone) (PLECs) were synthesized with varied D,L-lactide (LA) content and different molecular weights (20 and 50 kDa). Polymer ratios, particularly the content of LA, had significant effect on the release of trypan blue. A lower trypan blue release rate was observed from monolithic rods composed of PLECs with higher CL/LA ratio. High LA content in polymer rod led to increase of the hydrophilicity of the polymer rod and the decrease of CL content resulted in the increase of the hydrophilicity of PLECs and hydrolysis rate. Spin-coating technique was employed to coat PCL-b-PEG-b-PCL membrane on PLEC rod with controlled thickness. Results showed that membrane encased rods can produce different release pattern including delayed release, zero-ordered release and burst release depending on the types of inner rod and membrane. Results for this study indicated that PLEC rods could provide the zero-order release profile of highly water-soluble molecules. Moreover, the longer lag phase was observed at higher thickness. These results suggest that these polymer rods were potential drug delivery systems that can provide controlled drug release profiles. [ABSTRACT FROM AUTHOR]

Copolymers of (D,L-lactide-random-ε-caprolactone)-block-poy(ethylene glycol)-block-(D,L-lactide-random-ε-caprolactone) or PLEC were explored as materials for injectable drug delivery system. A series of six PLECs were successfully synthesized with varied D,L-lactide (LA) content (0, 10 and 20%) and molecular weight (20 and 50 kDa). All polymers were able to form depots with more than 90% encapsulation efficiency of trypan blue leading to the loading density as high as 27% w/w. The variation of trypan blue loading, LA content and molecular weight were found to have profound effects on trypan blue release profiles. Even though, GPC and SEM confirmed the higher degradation of PLEC chains, trypan blue release rate and burst release was greater as the content of hydrophilic moiety, i.e. LA, was decreased. This was primarily due to the smooth and dense surface and cross-section of PLEC depots. The results from this study suggest a possible application of these depots as injectable, self-solidifying drug delivery systems. [ABSTRACT FROM AUTHOR]

We describe the development of polymer implants that were designed to solidify once injected into rat brains. These implants comprised of glycofurol and copolymers of d, l-lactide (LA), ε-caprolactone and poly(ethylene glycol) (PLECs). Scanning electron microscopy (SEM) and gel permeation chromatography (GPC) showed that the extent of implant degradation was increased with LA content in copolymers. SEM analysis revealed the formation of porosity on implant surface as the degradation proceeds. PLEC with 19.3% mole of LA was chosen to inject in rat brains at the volume of 10, 25 and 40 μl. Body weights, hematological and histopathological data of rats treated with implants were evaluated on day 3, 6, 14, 30 and 45 after the injection. Polymer solution at the injection volume of 10 μl were tolerated relatively well compared to those of 25 and 40 μl as confirmed by higher body weight and healing action (fibrosis tissue) 30 days after treatment. The results from this study suggest a possible application as drug delivery systems that can bypass the blood brain barrier. [ABSTRACT FROM AUTHOR]

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with β-1apachone (β-1ap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between β-1ap and four cyclodextrins (α-, β-, γ-, and HPβ-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and [sup1]H-NMR spectroscopy. Biologic activity and bioavailability of β-lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that β-lap solubility increased in a linear fashion as a function of α-, β-, or HPβ-CD concentrations but not γ-CD. Maximum solubility of β-1ap was achieved at 16.0 mg/ml or 66.0 mM with HPβ-CD. Fluorescence and [sup1]H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between β-CD and HPβ-CD with β-lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of β-1ap in β-CD or HPβ-CD inclusion complexes (TD[sub50] = 2.1 μM). Animal studies in mice showed that the LD[sub50] value of β-1ap in an HPβ-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of β-1ap with HPβ-CD offers a major improvement in drug solubility and bioavailability. [ABSTRACT FROM AUTHOR]

Glucose metabolism of cancer can be used as a strategy to target cancer cells which exhibit altered glycolytic rate. The facilitated glucose transporter (Glut) plays an important role in enhancement glycolytic rate resulting in increased glucose uptake into cancer cells. 18FGD-PET image is an example for using Glut as a targeting to diagnose the high glycolytic rate of tumor. Thus, Glut may be adapted to target cancer cells for drug delivery system. Herein, biodegradation polymeric micelles target cancer cells by Glut was fabricated. The amphiphilic block copolymer of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) was synthesized where terminal group of the PEG chain was installed with glucose molecules. The 1H-NMR confirmed the existence of glucose moiety from two distinct peaks (5.2 and 4.7 ppm) of protons at anomeric carbon of glucose. Glucose-PEG-b-PCL spontaneously forms micelles in an aqueous solution. The size and zeta potential were 22 nm and -7 mv, respectively. Glucose-micelles have high stability, and no evidence of cytotoxicity was found after incubation for 7 days. Doxorubicin, used as a fluorescent probe, was loaded into glucose-micelles. The enhanced amount of doxorubicin as a result of glucose-micelles in PC-3, MCF-7 and HepG2 was evaluated by fluorescence microscopy and flow cytometer. Glucose molecules on the surface of micelles increased internalization and enhanced uptake of micelles via bypassing endocytosis pathway. These results show the use of glucose as a targeting ligand on the micelle surface to target cancer cells via Glut. [ABSTRACT FROM AUTHOR]

A correction to the article "Development of antimicrobial coating by layer-by-layer dip coating of chlorhexidine-loaded micelles" that was published in the July 06, 2017 issue is presented.