ABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Cisplatin/administration & dosage , Drug Carriers/administration & dosage , Micelles , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Cisplatin/pharmacokinetics , Cisplatin/toxicity , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Female , Hemolysis/drug effects , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Nude , Nanomedicine , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Polyethylene Glycols/chemistry , Polymethacrylic Acids/chemistry , Tissue Distribution/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Benefits of the frequently prescribed platinum (II) chemotherapy drugs are compromised by undesirable side effects, poor pharmacokinetics and development of drug resistance. Polymer micelles derived from amphiphilic block copolymers, offer a novel macromolecular platform for carrier based delivery of such compounds. Soft polymeric nanocarriers were synthesized by template-assisted method involving condensation of the poly(ethylene oxide)-b-polymethacrylate anions by metal ions into core-shell block ionomer complex micelles followed by chemical cross-linking of the polyion chains in the micelle cores. The resulting micelles can efficiently incorporate cisplatin with a high loading capacity (up to 42% w/w). Core cross-linking stabilized the micelles against structural disintegration and prevented premature drug release. The reversible cisplatin entrapment involved the carboxylate groups of the micellar core. The drug was released in a pH-responsive manner, without loss of its biological activity. The stable cross-linked polymer micelles can potentially improve platinum (II) drug disposition with improved therapeutic potential.
Subject(s)
Antineoplastic Agents/administration & dosage , Cisplatin/administration & dosage , Delayed-Action Preparations/chemistry , Micelles , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/pharmacology , Cross-Linking Reagents/chemistry , Female , Humans , Hydrogen-Ion Concentration , Neoplasms/drug therapyABSTRACT
A novel linear multifunctional polyethylene glycol (PEG)-dexamethasone (Dex) conjugate (click PEG-Dex) was synthesized using facile Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a click reaction). Dex was conjugated to the click PEG via an acid-labile hydrazone bond to allow the drug release in a pathophysiological environment. To evaluate click PEG's potential as a versatile drug delivery platform, the click PEG-Dex conjugates were tested in an adjuvant-induced arthritis (AA) rat model. In vivo optical imaging data confirmed the arthrotropism of the conjugates in the arthritic rats. A long-term treatment study revealed that a single click PEG-Dex conjugate administration provided sustained (>15 days) amelioration of ankle joint inflammation to the AA rats. Treatment with an equivalent dose of dexamethasone phosphate sodium (free Dex) only provided temporal resolution of the arthritis, which recurred upon treatment withdrawal. Further histological and bone mineral density comparison between the ankle joints from both click PEG-Dex and free Dex treatment groups confirmed the superior anti-inflammatory and disease modifying effects of the novel polymer-drug conjugates.
