66 research outputs found
Nanocarriers for delivery of platinum anticancer drugs
Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs
Modification of Daunorubicin-GnRH-III Bioconjugates With Oligoethylene Glycol Derivatives to Improve Solubility and Bioavailability for Targeted Cancer Chemotherapy
Daunorubicin-GnRH-III bioconjugates have recently been developed as drug delivery systems
with potential applications in targeted cancer chemotherapy. In order to improve their
biochemical properties, several strategies have been pursued: (1) incorporation of an
enzymatic cleavable spacer between the anticancer drug and the peptide-based targeting
moiety, (2) peptide modification by short chain fatty acids or (3) attachment of two anticancer
drugs to the same GnRH-III derivative. Although these modifications led to more potent
bioconjugates, a decrease in their solubility was observed. Here we report on the design,
synthesis and biochemical characterization of daunorubicin-GnRH-III bioconjugates with
increased solubility, which could be achieved by incorporating oligoethylene glycol-based
spacers in their structure. First, we have evaluated the effect of an oligoethylene glycol-based
spacer on the solubility, enzymatic stability/degradation, cellular uptake and in vitro cytostatic
effect of a bioconjugate containing only one daunorubicin attached through a GFLG
tetrapeptide spacer to the GnRH-III targeting moiety. Thereafter, more complex compounds
containing two copies of daunorubicin, GFLG spacers as well as Lys(nBu) in position 4 of
GnRH-III were synthesized and biochemically characterized. Our results indicated that all
synthesized oligoethylene glycol-containing bioconjugates had higher solubility in cell culture
medium than the unmodified analogs. They were degraded in the presence of rat liver
lysosomal homogenate leading to the formation of small drug containing metabolites. In the
case of bioconjugates containing two copies of daunorubicin, the incorporation of
oligoethylene glycol-based spacers led to increased in vitro cytostatic effect on MCF-7 human
breast cancer cells
Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice
Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery
Localized Increased Permeability of Blood–Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination
The development of new neurotherapeutics depends on appropriate animal models being chosen in preclinical studies. The cuprizone model is an effective tool for studying demyelination and remyelination processes in the brain, but blood–brain barrier (BBB) integrity in the cuprizone model is still a topic for debate. Several publications claim that the BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could explain the increased BBB permeability. In this study, we aim to analyze the permeability of the BBB for different macromolecules, particularly antibody conjugates, in a cuprizone-induced model of demyelination. We compared the traditional approach using Evans blue injection with subsequent dye extraction and detection of antibody conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in the cuprizone model. First, we validated our model of demyelination by performing T2-weighted MRI, diffusion tensor imaging, quantitative rt-PCR to detect changes in mRNA expression of myelin basic protein and proteolipid protein, and Luxol fast blue histological staining of myelin. Intraperitoneal injection of Evans blue did not result in any differences between the fluorescent signal in the brain of healthy and cuprizone-treated mice (IVIS analysis with subsequent dye extraction). In contrast, intravenous injection of antibody conjugates (anti-GFAP or non-specific IgG) after 4 weeks of a cuprizone diet demonstrated accumulation in the corpus callosum of cuprizone-treated mice both by contrast-enhanced MRI (for gadolinium-labeled antibodies) and by fluorescence microscopy (for Alexa488-labeled antibodies). Our results suggest that the methods with better sensitivity could detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that questioned BBB integrity in the cuprizone model and demonstrate the possibility of delivering antibody conjugates to the corpus callosum of cuprizone-treated mice
LHRH-Targeted Nanogels as a Delivery System for Cisplatin to Ovarian Cancer
Targeted
drug delivery using multifunctional polymeric nanocarriers
is a modern approach for cancer therapy. Our purpose was to prepare
targeted nanogels for selective delivery of chemotherapeutic agent
cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor
overexpressing tumor <i>in vivo</i>. Building blocks of
such delivery systems consisted of innovative soft block copolymer
nanogels with ionic cores serving as a reservoir for cisplatin (loading
35%) and a synthetic analogue of LHRH conjugated to the nanogels via
poly(ethylene glycol) spacer. Covalent attachment of (d-Lys6)-LHRH
to nanogels was shown to be possible without loss in either the ligand
binding affinity or the nanogel drug incorporation ability. LHRH-nanogel
accumulation was specific to the LHRH-receptor positive A2780 ovarian
cancer cells and not toward LHRH-receptor negative SKOV-3 cells. The
LHRH-nanogel cisplatin formulation was more effective and less toxic
than equimolar doses of free cisplatin or untargeted nanogels in the
treatment of receptor-positive ovarian cancer xenografts in mice.
Collectively, the study indicates that LHRH mediated nanogel-cisplatin
delivery is a promising formulation strategy for therapy of tumors
that express the LHRH receptor
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