ABSTRACT
A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.
Subject(s)
Doxorubicin/administration & dosage , Drug Delivery Systems/methods , Micelles , Paclitaxel/administration & dosage , Prodrugs/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Disulfides/chemistry , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Drug Liberation , Female , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Oxidation-Reduction , Paclitaxel/chemistry , Paclitaxel/pharmacokinetics , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Propionates/chemistry , Tumor Burden/drug effects , Vitamin E/chemistryABSTRACT
In the present study, polyion complex micelles based on pluronic F127-chitosan (F127-CS) and sodium deoxycholate (NaDC) were prepared to improve the oral absorption of tacrolimus (FK506) by increasing its aqueous solubility and enhancing its absorption in the gastrointestinal (GI) tract. FK506-loaded F127-CS/NaDC micelles were prepared by the thin film hydration method and had a high drug-loading capacity (8.93±1.47%) and a small particle size (55.77±2.23 nm). The low critical micelle concentration (2.65 × 10-3 mol/L) and the stability test results indicated that F127-CS/NaDC micelles have an enhanced stability against the dilution of GI fluid or blood. Tests of cell uptake showed that F127-CS/NaDC micelles exerted a comparable P-glycoprotein inhibition to verapamil. Compared with FK506 solution, the time to peak (tmax) of FK506 in F127-CS/NaDC micelles decreased from 3 to 1 h and the half-life was prolonged from 16.09 h to 18.00 h. Moreover, drug-time area under the curve was increased by 39.3%, from 533.79 to 742.11 ng/mL·h, which indicated enhanced oral absorption of FK506 in FK506-loaded F127-CS/NaDC micelles. Furthermore, the immunosuppressive effect of FK506-loaded F127-CS/NaDC micelles in a rat liver transplantation model was better than that of FK506 solution. All these results showed that FK506-loaded F127-CS/NaDC micelles are a promising approach for oral delivery of FK506.
ABSTRACT
Nanogel-based multifunctional drug delivery systems, especially hybrid nanogels and multicompartment nanogels have drawn more and more extensive attention from the researchers in pharmacy because it can result in achieving a superior functionality through the synergistic property enhancement of each component. The unique hybrid and compartmentalized structures provide the great potential for co-delivery of multiple agents even the multiple agents with different physicochemical properties. Otherwise the hybrid nanogel encapsulating optical and magnetic resonance imaging contrast can be utilized in imaging technique for disease diagnosis. More importantly through nanogel-based multifunctional drug delivery systems the stimuli-responsive features might be easily employed for the design of targeted release of drug. This review summarizes the construction of diverse hybrid nanogels and multicompartment nanogels. The application in co-delivery of multiple agents and imaging agents for diagnosis as well as the application in the design of stimuli-responsive multifunctional nanogels as drug delivery are also reviewed and discussed. The future prospects in application of multifunctional nanogels will be also discussed in this review.
Subject(s)
Drug Delivery Systems/methods , Magnetic Resonance Imaging/methods , Nanostructures , Tomography, Optical Coherence/methods , Animals , Gels/chemical synthesis , Gels/chemistry , Gels/therapeutic use , Humans , Nanostructures/chemistry , Nanostructures/therapeutic useABSTRACT
Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems , Nanoparticles/administration & dosage , Neoplasms/therapy , Prodrugs/administration & dosage , Combined Modality Therapy , Humans , Nanoparticles/chemistryABSTRACT
In present study, two types of micelles based on sodium cholate (NaC) were prepared through non-covalent bonding interaction and the potential of micelles as oral drug delivery systems for paclitaxel (PTX) was evaluated. Pluronic-chitosan (F127-CS) and Pluronic-poly (acrylic acid) (F127-PAA) copolymers were synthesized. Electrostatic interaction and hydrogen bond were used to prepare F127-CS/NaC micelles and F127-PAA/NaC micelles, respectively. The physicochemical characteristics of micelles were determined. An average diameter of 67.5 nm and unimodal pattern of size distribution were observed for F127-CS/NaC micelles. While for F127-PAA/NaC micelles, an average diameter of 85.89 nm and non-unimodal pattern of size distribution were observed. The results revealed that F127-CS/NaC micelles were more integrated than F127-PAA/NaC micelles. Further experiments showed that the F127-CS/NaC micelles had a higher drug-loading content of 12.8% and a lower critical micelle concentration (CMC) of 2.5 × 10-3 mol/L compared with F127-PAA/NaC micelles. In vitro cytotoxicity analysis demonstrated that the PTX-loaded F127-CS/NaC micelles were of great efficiency in inhibiting the growth of drug-resistant breast cancer MCF-7 cells (MCF-7/Adr). The intragastric administration of the PTX-loaded F127-CS/NaC micelles in rats provided a 4.33-fold higher absolute bioavailability compared to commercial Taxol®, indicating an efficient oral absorption of PTX delivered by micelles. These findings signify that F127-CS/NaC micelle may be a promising carrier for the delivery of PTX.
