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1.
Int J Nanomedicine ; 14: 7891-7901, 2019.
Article in English | MEDLINE | ID: mdl-31632006

ABSTRACT

PURPOSE: The improvement of postoperative pain control plays an important role in recovery outcomes and patient satisfaction. Multilamellar vesicles ropivacaine, MVR, is being developed to sustain the release of ropivacaine in situ while maintaining the local concentration of ropivacaine within the therapeutic window. METHODS: These studies summarized the processes of MVR formulation development and the evaluation of its releasing profile in vitro and the pharmacokinetics and anesthetic effect in vivo. RESULTS: The MVR demonstrates a sustained-release profile in an in vitro serum environment model after 24 hrs of incubation which translates in the in vivo rat pharmacokinetic profile of ropivacaine as a prolonged half-life that is 10-fold longer in duration than plain ropivacaine solution. The anesthetic effect of single-dose MVR is apparent by providing a prolonged analgesia effect compared to plain ropivacaine solution in an in vivo guinea pig pin-prick wheal model after a single intracutaneous injection. From a safety evaluation, MVR is well tolerated after a subcutaneously injection at a dose level of 20 mg/kg in rats, with no observable changes in clinical observation, body weight, organ weight, hematology and serum chemistry analysis. CONCLUSION: These results suggest that single administration of MVR is a promising candidate in postoperative pain management.


Subject(s)
Drug Carriers/chemistry , Drug Compounding , Pain Management , Ropivacaine/therapeutic use , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacokinetics , Anesthetics, Local/therapeutic use , Animals , Drug Liberation , Female , Guinea Pigs , Humans , Hydrogen-Ion Concentration , Male , Organ Size , Pain, Postoperative/drug therapy , Rats, Sprague-Dawley , Ropivacaine/administration & dosage , Ropivacaine/adverse effects , Ropivacaine/pharmacokinetics , Time Factors
2.
Nanotechnology ; 25(29): 295102, 2014 Jul 25.
Article in English | MEDLINE | ID: mdl-24990295

ABSTRACT

Gold nanoparticles (AuNPs) are widely applied to the diagnosis and treatment of cancer and can be modified to contain target-specific ligands via gold-thiolate bonding. This study investigated the pharmacokinetics and microdistribution of antibody-mediated active targeting gold nanoparticles in mice with subcutaneous lung carcinoma. We conjugated AuNPs with cetuximab (C225), an antibody-targeting epidermal growth factor receptor (EGFR), and then labeled with In-111, which created EGFR-targeted AuNPs. In vitro studies showed that after a 2 h incubation, the uptake of C225-conjugated AuNPs in high EGFR-expression A549 cells was 14.9-fold higher than that of PEGylated AuNPs; furthermore, uptake was also higher at 3.8-fold when MCF7 cells with lower EGFR-expression were used. MicroSPECT/CT imaging and a biodistribution study conducted by using a A549 tumor xenograft mouse model provided evidence of elevated uptake of the C225-conjugated AuNPs into the tumor cells as a result of active targeting. Moreover, the microdistribution of PEGylated AuNPs revealed that a large portion of AuNPs remained in the tumor interstitium, whereas the C225-conjugated AuNPs displayed enhanced internalization via antibody-mediated endocytosis. Our findings suggest that the anti-EGFR antibody-conjugated AuNPs are likely to be a plausible nano-sized vehicle for drug delivery to EGFR-expressing tumors.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Carcinoma/drug therapy , Lung Neoplasms/drug therapy , Nanoconjugates/therapeutic use , Animals , Antibodies, Monoclonal, Humanized/chemistry , Antineoplastic Agents/chemical synthesis , Cetuximab , Disease Models, Animal , Female , Gold/chemistry , Gold/pharmacokinetics , Mice , Mice, Inbred BALB C , Microspectrophotometry , Nanoconjugates/chemistry , Surface Plasmon Resonance , Tumor Cells, Cultured
3.
Bioorg Med Chem Lett ; 23(23): 6486-91, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24119556

ABSTRACT

Two galactose derivatives, a monovalent (99m)Tc-MAMA-MGal galactoside and a divalent (99m)Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the (99m)Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that (99m)Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction.


Subject(s)
Asialoglycoprotein Receptor/analysis , Galactose/chemical synthesis , Liver Cirrhosis/diagnostic imaging , Technetium Compounds/chemical synthesis , Animals , Disease Models, Animal , Galactose/chemistry , Mice , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Technetium Compounds/chemistry , Tomography, Emission-Computed, Single-Photon/methods
4.
Appl Radiat Isot ; 80: 88-94, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23850887

ABSTRACT

A copolymer of poly(ethylene glycol)-b-poly(caprolactone) (PEG-PCL) was modified with a benzyl moiety and labeled with I-131. A micelle system, (131)I-benzyl-micelles, formed from (131)I-benzyl-PEG-PCL and PEG-PCL-PC, was created and used for in vitro characterization and in vivo evaluation. Administration of (131)I-benzyl-micelles to a colon carcinoma-bearing mouse model gives a 4.9-fold higher tumor-to-muscle ratio at 48 h post-injection than treatment with the unimer (131)I-benzyl-PEG-PCL. Scintigraphic imaging, biodistribution results and pharmacokinetical evaluation all demonstrated that (131)I-benzyl-micelles are a plausible radioactive surrogate for PEG-PCL copolymer micelles. Modifying the amphiphilic copolymer with a benzyl moiety and labeled it with iodine-131 should make possible the real-time and noninvasive evaluation of the pharmacokinetics of copolymer micelles in vivo.


Subject(s)
Colonic Neoplasms/metabolism , Disease Models, Animal , Micelles , Polyesters/pharmacokinetics , Polyethylene Glycols/pharmacokinetics , Animals , Male , Mice , Mice, Inbred BALB C , Radionuclide Imaging , Tissue Distribution
5.
PLoS One ; 8(5): e63078, 2013.
Article in English | MEDLINE | ID: mdl-23675454

ABSTRACT

PURPOSE: PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR) effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. METHODS: Empty PEGylated liposomes (NanoX) and those encapsulated with VNB (NanoVNB) were labeled with In-111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%). BALB/c mice bearing either small (58.4±8.0 mm(3)) or large (102.4±22.0 mm(3)) C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging) and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. RESULTS: The biodistribution study of InVNBL revealed a clear inverse correlation (r (2) = 0.9336) between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug) showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only) and InNanoX (radionuclide only). Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. CONCLUSION: The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Tumor Burden/drug effects , Vinblastine/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Body Weight , Cell Line, Tumor , Colonic Neoplasms/mortality , Diagnostic Imaging , Disease Models, Animal , Drug Administration Schedule , Liposomes/chemistry , Luminescent Measurements , Male , Mice , Polyethylene Glycols/chemistry , Tomography, Emission-Computed , Vinblastine/administration & dosage , Vinblastine/pharmacokinetics , Vinorelbine
6.
Bioorg Med Chem Lett ; 23(11): 3180-5, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23628334

ABSTRACT

This study evaluated the tumor targeting and therapeutic efficacy of a novel theranostic agent (131)I-labeled immuno-gold-nanoparticle ((131)I-C225-AuNPs-PEG) for high epidermal growth factor receptor (EGFR)-expressed A549 human lung cancer. Confocal microscopy demonstrated the specific uptake of C225-AuNPs-PEG in A549 cells. (131)I-C225-AuNPs-PEG induced a significant reduction in cell viability, which was not observed when incubated with AuNPs-PEG and C225-AuNPs-PEG. MicroSPECT/CT imaging of tumor-bearing mice after intravenous injection of (123)I-C225-AuNPs-PEG revealed significant radioactivity retention in tumor suggested that (131)I-labeled C225-conjugated radioimmuno-gold-nanoparticles may provide a new approach of targeted imaging and therapy towards high EGFR-expressed cancers.


Subject(s)
Antibodies, Monoclonal, Humanized/chemistry , Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Gold/chemistry , Metal Nanoparticles/chemistry , Radiopharmaceuticals/chemistry , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/toxicity , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Cetuximab , Disease Models, Animal , Drug Evaluation, Preclinical , ErbB Receptors/metabolism , Humans , Injections, Intravenous , Iodine Radioisotopes/chemistry , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/drug therapy , Mice , Microscopy, Confocal , Polyethylene Glycols/chemistry , Radiopharmaceuticals/therapeutic use , Radiopharmaceuticals/toxicity , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Transplantation, Heterologous
7.
Bioorg Med Chem ; 21(4): 912-21, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23321012

ABSTRACT

Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P <0.0001) was observed using confocal microscopy when co-incubated with 0.5µM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P <0.01) at 30min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30min post-injection) of hepatic fibrosis mice derived from both microPET imaging and biodistribution study were significantly lower (P <0.01) than those of normal mice. The pharmacokinetic parameters (T(1/2)α, T(1/2)ß, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of (18)F-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that (18)F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction.


Subject(s)
Asialoglycoprotein Receptor/chemistry , Benzamides/chemistry , Galactose/analogs & derivatives , Liver Cirrhosis/diagnostic imaging , Radiopharmaceuticals/chemistry , Animals , Asialoglycoprotein Receptor/metabolism , Benzamides/pharmacokinetics , Disease Models, Animal , Fluorine Radioisotopes/chemistry , Galactose/pharmacokinetics , Half-Life , Hep G2 Cells , Humans , Liver Cirrhosis/metabolism , Mice , Microscopy, Confocal , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution
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