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Biomedical subjects

Jinming Gao

Publications and source records attributed to Jinming Gao.

At least 19 recordsLinked to original sources
PubMed2007

Genetic variations of the CDC2L2 gene are associated with type 2 diabetes in a Han Chinese cohort.

OBJECTIVE: The purpose of the present study was to study the potential association of CDC2L2 variations with type 2 diabetes (T2D). METHODS: SNPs (single nucleotide polymorphisms) were extensively screened across the CDC2L2 gene by the site-specific PCR method ARMS (Amplification Refractory Mutation System). The identified novel polymorphisms were further evaluated in a Han Chinese cohort comprising of 467 patients with diabetes and 569 nondiabetic controls. In addition, 76 parent-offspring trios were also included in this association study. The case-control and TDT/sibTDT studies are applied for association analysis in this study. RESULTS: Seven loci (rs1059831, SNP33, rs7528782, SNP11, SNP36, rs11488590 and SNP30) were shown to be significantly associated with T2D in unrelated individuals (p < 0.05). When individuals were stratified by age, sex and body mass index (BMI), the SNP11 was shown to be strongly associated with female patients with T2D, patients whose age was over 45 years and individuals whose BMI was less than 23 (p = 0.018, 0.011 and 0.0089, respectively). However, it was not replicated in the family-based TDT/sibTDT analysis (p = 0.085, OR = 0.63 (CI 95% 0.34-1.06)). CONCLUSION: Our data suggested that the CDC2L2 gene may contribute to the susceptibility of type 2 diabetes in the northern Han Chinese population, but further studies are needed to replicate these findings.

Adult↗
PubMed2007

Antitumor efficacy and local distribution of doxorubicin via intratumoral delivery from polymer millirods.

The purpose of this study was to evaluate the antitumor efficacy and local drug distribution from doxorubicin-containing poly(D,L-lactide-co-glycolide) (PLGA) implants for intratumoral treatment of liver cancer in a rabbit model. Cylindrical polymer millirods (length 8 mm, diameter 1.5 mm) were produced using 65% PLGA, 21.5% NaCl, and 13.5% doxorubicin. These implants were placed in the center of VX2 liver tumors (n = 16, 8 mm in diameter) in rabbits. Tumors were removed 4 and 8 days after millirod implantation, and antitumor efficacy was assessed using tumor size measurements, tumor histology, and fluorescent measurement of drug distribution. The treated tumors were smaller than the untreated controls on both day 4 (0.17 +/- 0.06 vs. 0.31 +/- 0.08 cm(2), p = 0.048) and day 8 (0.14 +/- 0.04 vs. 1.8 +/- 0.8 cm(2), p = 0.025). Drug distribution profiles demonstrated high doxorubicin concentrations (>1000 microg/g) at the tumor core at both time points and drug penetration distances of 2.8 and 1.3 mm on day 4 and 8, respectively. Histological examination confirmed necrosis throughout the tumor tissue. Biodegradable polymer millirods successfully treated the primary tumor mass by providing high doxorubicin concentrations to the tumor tissue over an eight day period.

Absorbable Implants↗
PubMed2007

Combined radiofrequency ablation and doxorubicin-eluting polymer implants for liver cancer treatment.

Previously, biodegradable polymer implants (polymer millirods) to release chemotherapeutic agents directly into tumors have been developed. The purpose of this study is to evaluate local drug distribution from these implants in liver tumors treated with radiofrequency (RF) ablation and determine if the implants provide a therapeutic improvement over RF ablation alone. Cylindrical implants were fabricated using 65% poly(D,L-lactide-co-glycolide) (PLGA), 21.5% NaCl, and 13.5% doxorubicin. Control or drug-containing millirods were implanted inside VX2 liver tumors (11 mm diameter) in rabbits after RF ablation. Therapeutic efficacy was assessed 4 and 8 days after treatment using tumor size, histology, and fluorescence measurement of drug distribution. Tumors in both test groups recurred at the boundary of the ablated region. Therapeutic doxorubicin concentrations were found in more than 80% of the ablated area, but concentrations declined rapidly at the boundary between normal and ablated tissue. This region was characterized by a developing fibrous capsule with resolving inflammation, which restricted drug transport out of the ablated zone. The intratumoral doxorubicin implants delivered high concentrations of drug within the ablated region but only limited amounts outside the ablation zone. Future studies will focus on overcoming the fibrotic transport barrier and enhancing drug delivery to the periphery of the ablation region to prevent tumor progression.

Absorbable Implants↗
PubMed2006

Local release of dexamethasone from polymer millirods effectively prevents fibrosis after radiofrequency ablation.

Recent studies show that after radiofrequency (RF) ablation, fibrosis occurs at the ablation boundary, hindering anticancer drug transport from a locally implanted polymer depot to the ablation margin, where tumors recur. The purpose of this study is to investigate strategies that can effectively deliver dexamethasone (DEX), an anti-inflammatory agent, to prevent fibrosis. Polymer millirods consisting of poly(D,L-lactide-co-glycolide) (PLGA) were loaded with either DEX complexed with hydroxypropyl beta-cyclodextrin (HPbeta-CD), or an NaCl and DEX mixture. In vitro release studies show that DEX complexed with HPbeta-CD released 95% of the drug after 4 days, compared to 14% from millirods containing NaCl and DEX. Rat livers underwent RF ablation and received either DEX-HPbeta-CD-loaded millirods, PLGA millirods with an intraperitoneal (i.p.) DEX injection, or control PLGA millirods alone. After 8 days in vivo, heightened inflammation and the appearance of a well-defined fibrous capsule can be observed in both the control experiments and those receiving a DEX injection (0.29 +/- 0.08 and 0.26 +/- 0.07 mm in thickness, respectively), with minimal inflammation and fibrosis present in livers receiving DEX millirods (0.04 +/- 0.01 mm). Results from this study show that local release of DEX prevents fibrosis more effectively than a systemic i.p. injection.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2006

Mornings with Art, lessons learned: feedback regulation, restriction threshold biology, and redundancy govern molecular stress responses.

Work from the laboratory of Dr. Arthur B. Pardee has highlighted basic principles that govern cellular and molecular biological processes in living cells. Among the most important governing principles in cellular and molecular responses are: (i) threshold "restriction" responses, wherein a level of response is reached and a "point of no return" is achieved; (ii) feedback regulation; and (iii) redundancy. Lessons learned from the molecular biology of cellular stress responses in mammalian cancer versus normal cells after ionizing radiation (IR) or chemotherapeutic agent exposures reveal similar instances of these guiding principles in mammalian cells. Among these are the: (i) induction of cell death responses by beta-lapachone (beta-lap), a naphthoquinone anti-tumor agent that kills cancer cells via an NQO1 (i.e., X-ray-inducible protein-3, xip3)-dependent mechanism; (ii) induction of secretory clusterin (sCLU) in response to TGF-beta1 exposure, and the ability of induced sCLU protein to down-regulate TGF-beta1 signaling; and (iii) induction of DNA mismatch repair-dependent G(2) cell cycle checkpoint responses after exposure to alkylating agents. We have learned these lessons and now adopted strategies to exploit them for improved therapy. These examples will be discussed and compared to the pioneering findings of researchers in the Pardee laboratory over the years.

Apoptosis↗
PubMed2006

Modulating beta-lapachone release from polymer millirods through cyclodextrin complexation.

Beta-lapachone (beta-lap) is a novel anticancer agent that kills tumors overexpressing the NADPH: quinone oxidoreductase enzyme. However, poor aqueous solubility and low bioavailability hinder its therapeutic applications. Herein we describe the development of poly(D,L-lactide-co-glycolide) (PLGA) polymer millirods for local delivery of beta-lap. The objective was to investigate the use of beta-lap inclusion complexes with cyclodextrins (CDs) to control beta-lap release kinetics from PLGA millirods. Differential scanning calorimetry was performed to measure drug/polymer interactions, complexation efficiency with different CDs, and complex/polymer interactions. beta-Lap was found to have a solid-state solubility of 13% in PLGA. beta-Lap dissolution in PLGA matrix lowered the glass transition temperature of PLGA from 44 to 31 degrees C, and led to a slow release of beta-lap (8.8+/-1.2% release after 22 days). For beta-lap and CD interactions, increasing complexation efficiency was observed in the order of alpha-CD, gamma-CD, and beta-CD. beta-Lap complexation with hydroxypropyl-beta-cyclodextrin (HPbeta-CD) prevented drug dissolution in PLGA, and led to fast release (79.6+/-2.1% after 2 days). Sustained drug release was achieved when beta-lap was complexed with alpha-CD or gamma-CD. These data demonstrate the ability to tailor beta-lap release kinetics via CD complexation, providing exciting opportunities for the use of beta-lap-millirods for intratumoral drug delivery.

Antineoplastic Agents↗
PubMed2006

Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems.

We describe the development of multifunctional polymeric micelles with cancer-targeting capability via alpha(v)beta(3) integrins, controlled drug delivery, and efficient magnetic resonance imaging (MRI) contrast characteristics. Doxorubicin and a cluster of superparamagnetic iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence of cRGD on the micelle surface resulted in the cancer-targeted delivery to alpha(v)beta(3)-expressing tumor cells. In vitro MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and alpha(v)beta(3)-specific cytotoxic response of these multifunctional polymeric micelles.

Cell Line, Tumor↗
PubMed2005

Interactions between self-assembled polyelectrolyte shells and tumor cells.

Layer-by-layer self-assembled polyelectrolyte shells are a new class of micro/nanocapsules with unique physicochemical properties for potential applications in drug/gene delivery. The objective of this study was to investigate the interactions of polyelectrolyte shells ( approximately 1 mum in diameter) with MCF-7 breast cancer cells and identify key parameters that affect such interactions. Tailoring of surface properties of polyelectrolyte shells was achieved by choosing different outermost layer materials, including cationic polymers, anionic polymers, and lipid bilayers. Different surface compositions led to a wide range of electrostatic potentials from -46 to +47 mV in phophate-buffered saline buffer. Confocal microscopy studies showed that the polyelectrolyte shells were internalized into the cell cytoplasm, but not into the nuclei. Correlation of cell uptake with shell surface compositions was complicated by the adsorption of serum proteins on the surface of polyelectrolyte shells, particularly polycation-coated shells. To prevent protein adsorption, poly(ethylene glycol) (PEG) grafted poly(ethyleneimine) (PEI) copolymers (1:1, 1:5, 1:10 graft ratios) were synthesized and introduced on the shell surface. Shells coated with PEI-PEG copolymers effectively reduced protein adsorption whereas PEI-PEG copolymers with lower graft ratios achieved higher cell uptake efficiency after 24 h of incubation with MCF-7 cells.

Biocompatible Materials↗
PubMed2005

Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels.

beta-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 reduces beta-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta-lapachone. Thus, beta-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non-small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of beta-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to beta-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to beta-lapachone. Once converted, beta-lapachone derivatives caused NQO1-dependent, mu-calpain-mediated cell death in human cancer cells identical to that caused by beta-lapachone. Interestingly, coadministration of N-acetyl-l-cysteine, prevented derivative-induced cytotoxicity but did not affect beta-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of beta-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-l-cysteine, preventing their conversion to beta-lapachone. The use of beta-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.

Cell Division↗
PubMed2005

Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1.

NAD(P)H:quinone oxidoreductase (NQO1) is elevated in human pancreatic cancers. We hypothesized that beta-lapachone, a novel 1,2-naphthoquinone with potential antitumor activity in cancer cells expressing elevated levels of NQO1, would induce cytotoxicity in pancreatic cancer cells, wherein this two-electron reductase was recently found elevated. beta-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage- independent growth in soft agar. The cytotoxic in vitro effects of beta-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In preestablished human pancreatic tumor xenografts in nude mice, beta-lapachone demonstrated greater tumor growth inhibition when given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability. Due to the poor prognosis of patients with pancreatic cancer and the limited effectiveness of surgery, chemotherapy, and radiation therapy, treatment regimens based on sound, tumor-specific rationales are desperately need for this disease.

Aged↗
PubMed2005

Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation.

PURPOSE: To reveal the interaction between beta-lapachone (beta-lap) and ionizing radiation (IR) in causing clonogenic death in cancer cells and to elucidate the potential usefulness of beta-lap treatment in combination with radiotherapy of cancer. METHODS AND MATERIALS: FSaII tumor cells of C3H mice were used. The cytotoxicity of beta-lap alone or in combination with IR in vitro was determined using clonogenic survival assay method. The IR-induced changes in the expression and the enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1), a mediator of beta-lap cytotoxicity, were elucidated and the relationship between the NQO1 level and the sensitivity of cells to beta-lap was investigated. The combined effect of IR and beta-lap to suppress tumor growth was studied using FSaII tumors grown subcutaneously in the thigh of C3H mice. RESULTS: beta-Lap caused clonogenic death of FSaII tumor cells in vitro in a dose- and time-dependent manner. When cells were treated first with beta-lap and then exposed to IR in vitro, the resultant cell death was only additive. On the contrary, exposing cells to IR at 2.5 Gy first and then treating the cells with beta-lap killed the cells in a synergistic manner. Importantly, the 2.5 Gy cells were sensitive to beta-lap as long as 10 h after irradiation, which was long after the sublethal radiation damage was repaired. Irradiation of FSaII cells in vitro with 2.5 Gy significantly increased the expression and enzymatic activity of NQO1. The growth delay of FSaII tumors caused by an intraperitoneal injection of beta-lap in combination with 20 Gy irradiation of tumor was significantly greater than that caused by beta-lap or 20 Gy irradiation alone. CONCLUSION: The sensitivity of cells to beta-lap is dependent on NQO1 activity. IR caused a long-lasting increase in NQO1 activity in cancer cells, thereby sensitizing cells to beta-lap and treatment of experimental mouse tumors with IR and beta-lap suppressed tumor growth in a synergistic manner. The combination of beta-lap and radiotherapy is a potentially effective regimen for the treatment of human cancer.

Animals↗
PubMed2004

Micellar carriers based on block copolymers of poly(epsilon-caprolactone) and poly(ethylene glycol) for doxorubicin delivery.

Diblock copolymers of poly(epsilon-caprolactone) (PCL) and monomethoxy poly(ethylene glycol) (MPEG) with various compositions were synthesized. The amphiphilic block copolymers self-assembled into nanoscopic micelles and their hydrophobic cores encapsulated doxorubicin (DOX) in aqueous solutions. The micelle diameter increased from 22.9 to 104.9 nm with the increasing PCL block length (2.5-24.7 kDa) in the copolymer composition. Hemolytic studies showed that free DOX caused 11% hemolysis at 200 microg ml(-1), while no hemolysis was detected with DOX-loaded micelles at the same drug concentration. An in vitro study at 37 degrees C demonstrated that DOX-release from micelles at pH 5.0 was much faster than that at pH 7.4. Confocal laser scanning microscopy (CLSM) demonstrated that DOX-loaded micelles accumulated mostly in cytoplasm instead of cell nuclei, in contrast to free DOX. Consistent with the in vitro release and CLSM results, a cytotoxicity study demonstrated that DOX-loaded micelles exhibited time-delayed cytotoxicity in human MCF-7 breast cancer cells.

Antibiotics, Antineoplastic↗
PubMed2004

Effect of fibrous capsule formation on doxorubicin distribution in radiofrequency ablated rat livers.

In this study, we report the histological findings of a combined therapy using radiofrequency ablation and intratumoral drug delivery in rat livers, with special attention to wound-healing processes and their effects on drug transport in post-ablated tissue. Doxorubicin-loaded millirods were implanted in rat livers that had undergone medial lobe ablation. Millirods and liver samples were retrieved upon animal sacrifice at time points ranging from 1 h to 8 days. Results demonstrate a clearly defined area of coagulative necrosis within the ablation boundary. The wound-healing response, complete with the appearance of inflammatory cells, neovascularization, and the formation of a fibrous capsule, was also observed. At the 8-day time point, fluorescence imaging analysis showed a higher concentration of doxorubicin localized within the ablation region, with its distribution hampered primarily by fibrous capsule formation at the boundary. Given the variant nature of ablated liver, a mathematical model devised previously by our laboratory describes the data well up to 4 days, but loses reliability at 8 days. These results provide useful mechanistic insights into the wound-healing response after radiofrequency ablation and polymer millirod implantation, as well as the impact this natural corollary has on drug distribution.

Animals↗
PubMed2004

Quantitative computed tomography analysis of local chemotherapy in liver tissue after radiofrequency ablation.

RATIONALE AND OBJECTIVES: Computed tomography (CT) was used to noninvasively monitor local drug pharmacokinetics from polymer implants in rat livers before and following radiofrequency ablation. MATERIALS AND METHODS: Polymer matrixes containing carboplatin (a platinum-containing chemotherapeutic agent) were implanted into rat livers either immediately after radiofrequency ablation (n = 15) or without prior treatment (n = 15). The animals were divided into five subgroups (n = 3 per group) and subjected to a terminal CT scan at 6, 24, 48, 96, or 144 hours. Carboplatin concentration in tissue and within the implant matrix was correlated with CT intensity, and standard curves were produced for each environment. This correlation was used to evaluate the differences in drug transport properties between normal and ablated rat livers. A quantitative image analysis method was developed and used to evaluate the release rate and tissue distribution of carboplatin in normal and ablated liver tissue. The CT data were validated by previously reported atomic absorption spectroscopy measurement of implant and tissue drug levels. RESULTS: Correlation of carboplatin concentration and Hounsfield units results in a linear relationship with correlation coefficients (slopes) of 15 and 4 Hounsfield units/(mg/mL), for carboplatin in tissue and polymer, respectively. Noninvasive monitoring of local pharmacokinetics in normal and ablated tissues indicates that ablation before local carboplatin delivery increases the retention of carboplatin within the polymer matrix and drastically increases the drug retention in the ablated tissue volume (over 3-fold difference) resulting in a higher average dose to the surrounding tissue. At 1.6 mm from the implant boundary, carboplatin concentration is significantly higher in ablated tissue at 48, 96, and 144 hours (P <.05), and reaches 4.7 mg/mL in ablated tissue at 48 hours. In comparison, the concentration in normal liver at 1.6 mm reaches only 0.7 mg/mL at the same time point. The drug penetrates 3.1 mm in ablated liver compared with 2.3 mm in normal liver also at 48 hours. After 144 hours, the drug is still detected at 3.1 mm in ablated liver but not in normal liver. The differences are significant (P <.05) at both 48 and 144 hours. Correlation with chemical analysis suggests that CT data accurately predicts the drug pharmacokinetics in both ablated and normal livers. CONCLUSION: This work shows that X-ray CT imaging is a useful and promising technique for in vivo monitoring of the release kinetics of locally delivered radiopaque agents.

Animals↗
PubMed2004

Comparison of doxorubicin concentration profiles in radiofrequency-ablated rat livers from sustained- and dual-release PLGA millirods.

PURPOSE: To evaluate and compare the local pharmacokinetics of doxorubicin in radiofrequency (rf)-ablated rat livers after interstitial delivery from sustained- and dual-release poly(D,L-lactide-co-glycolide) (PLGA) millirods. METHODS: PLGA millirods with sustained- and dual-release kinetics (burst followed by sustained release) of doxorubicin were implanted in rf-ablated rat livers. Doxorubicin release kinetics in vivo were measured from explanted millirods by UV-Vis spectrophotometer over 8 days. Spatial distribution of doxorubicin in liver tissues was measured by fluorescence imaging. RESULTS: In the initial 24 h after millirod implantation, dual-release millirods released significantly more doxorubicin into liver tissues than the sustained millirods. Subsequently, both types of millirods provided comparable sustained-release kinetics over 8 days. With dual-release millirods, doxorubicin concentration and penetration distance in liver tissue increased more rapidly. To reach 30 microg/g doxorubicin concentration at the ablation boundary (targeted site of action), the time required was 6 days and 1.5 days for sustained- and dual-release millirods, respectively. CONCLUSIONS: Compared with sustained-release millirods, dual-release millirods provide a quick concentration elevation and sustaining of the drug concentration at the ablation boundary. Additionally, the steady-state drug concentration agrees well with model predictions based on previously determined transport parameters, which demonstrates the feasibility of rational design of drug formulations in polymer millirods.

Animals↗
PubMed2003

Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers.

The objective of this research was to quantify the key parameters governing the drug transport processes in radiofrequency (RF) thermoablated and non-ablated liver tissues. Experimentally, doxorubicin-containing polymer millirods were implanted in the ablated rat livers and spatial distribution of doxorubicin was measured by fluorescence imaging from 1 to 96 h after millirod implantation. At all time points, doxorubicin had significantly higher tissue penetration and retention in ablated tissues than in non-ablated tissues. A mathematical model was developed to quantitatively describe the transport processes in ablated and non-ablated rat livers. Based on the experimental data and mathematical models, the optimal estimates of apparent drug diffusivities in ablated and non-ablated tissues were 1.1 x 10(-7) and 6.7 x 10(-7) cm(2) s(-1), respectively, and the apparent drug elimination rate coefficient was 9.6 x 10(-4) s(-1) in non-ablated tissues. Results from this study contribute to the fundamental understanding of in vivo drug transport in liver tissues and provide the quantitative parameters for the rational design of polymer millirods for liver cancer treatment.

Algorithms↗
PubMed2003

Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin.

The complement anaphylatoxin C3a and its cellular seven-transmembrane segment receptor, C3aR, are implicated in a variety of pathological inflammatory processes. C3aR is a G-protein-coupled receptor with an exceptionally large second extracellular loop of 172 amino acids. Previously reported deletion studies have shown that at least part of this region plays a critical role in binding C3a. Our data now demonstrate that five tyrosines in the second extracellular loop of the C3aR are posttranslationally modified by the addition of sulfate. Blocking sulfation by mutation of tyrosine to phenylalanine at positions 184, 188, 317, and/or 318 does not affect ligand binding or signal transduction. However, when tyrosine 174 is mutated to phenylalanine, binding of native C3a is completely blocked. This variant efficiently mobilizes calcium in response to synthetic C3a agonist peptides, but not to native C3a. This finding is consistent with a two-site model of ligand association typical of many peptide ligand-receptor interactions and identifies sulfotyrosine 174 as the critical C3a docking site. Tyrosine sulfation in the amino-terminal extracellular domain has been shown to be important in several other seven-transmembrane segment receptors. Our data now demonstrate that tyrosine sulfate in other extracellular domains can function for ligand interactions as well.

Binding Sites↗