ABSTRACT
Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4.3 times less cytotoxic than gemcitabine, but exhibited 11-fold improvement in cellular uptake. Heat activation of the formulation led to a 56% rise in cytotoxicity causing it to outperform gemcitabine by 26%. In vivo the formulation outperformed free gemcitabine with a 62% reduction in tumor weight in pancreatic xenografts. This HNP formulation is the first of its kind and has displayed superior anti-cancer activity as compared to the current first line drug gemcitabine after heat mediated controlled release.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Deoxycytidine/analogs & derivatives , Maleimides/administration & dosage , Nanoparticles/administration & dosage , Pancreatic Neoplasms/drug therapy , Prodrugs/administration & dosage , Animals , Antimetabolites, Antineoplastic/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Deoxycytidine/administration & dosage , Deoxycytidine/chemistry , Drug Liberation , Female , Hot Temperature , Humans , Lasers , Maleimides/chemistry , Mice, Nude , Nanoparticles/chemistry , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/radiotherapy , Prodrugs/chemistry , Tumor Burden/drug effects , GemcitabineABSTRACT
Autotaxin is an extracellular phospholipase D that catalyzes the hydrolysis of lysophosphatidyl choline (LPC) to bioactive lipid lysophosphatidic acid (LPA). LPA has been implicated in many pathological processes relevant to cancer, including cell migration and invasion, proliferation, and survival. The most potent autotaxin inhibitor described to date is the LPA analogue S32826 (IC50 5.6 nM). S32826 and many other autotaxin inhibitors are notably lipophilic, creating a need to improve their physical properties. Polymers are becoming an increasingly useful tool in the delivery of drugs and have the potential to improve the properties of small molecules. Herein we report the synthesis of a S32826 dendrimer conjugate and its biological evaluation. The conjugate was found to inhibit autotaxin activity using two different substrates and to decrease the migration of an ovarian cancer cell line modified to overexpress autotaxin. Furthermore, the conjugate potentiated activation of caspase 3/7 induced by carboplatin.
ABSTRACT
Platinum-based anticancer agents such as cisplatin and carboplatin are in widespread clinical use but associated with many side effects. Improving the delivery of cytotoxic platinum compounds may lead to reduced side effects and achieve greater efficacy at lower doses. Polymer-based therapeutics have been investigated as potential drug delivery vehicles for platinum-based drugs. Against a background of the chemistry and pharmacology of cytotoxic platinum compounds, this review discusses the formation and properties of platinum-polymer complexes, dendrimers, micelles, and microparticulates.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Drug Delivery Systems , Platinum Compounds/administration & dosage , Platinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cisplatin/administration & dosage , Cisplatin/chemistry , Cisplatin/pharmacology , Cisplatin/therapeutic use , Humans , Platinum Compounds/chemistry , Platinum Compounds/therapeutic use , Polymers/chemistryABSTRACT
Hyperbranched polymers based on a polyether and polyester have been modified and used as macromolecular ligands for the anticancer drug cisplatin, giving controlled release of the drug over 7 days.
Subject(s)
Cisplatin/chemistry , Polymers/chemistry , Antineoplastic Agents/chemistry , Computers, MolecularABSTRACT
A method of calculating the bite (P-M-P) angle for dendritic ligands is reported. Diphenylphosphine terminated dendritic ligands were modified with either a single rhodium or a rhodium complex [HRh(CO)(2)] and molecular dynamics techniques used to run simulations to determine the dynamic bite angle (beta(d)) as a time averaged property. The effects of changing the composition of the dendritic branches is investigated and comparison with experimental hydroformylation data reveals that the dendrimer with the highest linear: branched ratio also has a dynamic bite angle closest to the theoretical ideal value of 120 degrees .
ABSTRACT
Molecular dynamics modelling has been used to simulate the structures of phopshine-functionalised, silsesquioxane-based dendrimers whose excellent catalytic properties have been previously demonstrated. The effect of changing the chemical composition of the dendrimer branches is simulated. The results indicate that adding a methylene unit to a branch increases the overall size of the dendrimer but replacing a methylene unit with an oxygen atom decreases the size of the dendrimer. The size and shape of the dendrimers have also been simulated on changing the temperature and polarity of the solvent. The distribution of phosphine groups on the exterior has also been modelled and this suggests that all are available for bonding to catalytic metals in all the compounds.
