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Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC 0-24h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere® . The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere®, without inducing histological changes in the major organs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multifunctional nanoparticles (NPs) have found important applications in diagnosis, chemotherapy, and image-guided surgery of tumors. In this work, we have developed polymeric theranostic NPs (PTNPs) containing the anticancer drug docetaxel (DTX), a fluorescent dye, and magnetic manganese oxide (MnO) NPs for dual modal imaging and chemotherapy. PTNPs ~150 nm in diameter were synthesized by co-loading hydrophobic DTX and MnO NPs ~5 nm in diameter, into the matrix of a fluorescent dye-labeled amphiphilic polymer. The PTNPs enabled high loading efficiency and sustained in vitro release of DTX. Energy-dependent cellular uptake and extended cytoplasmic retention of the PTNPs in MDA-MB-231 human breast cancer cells were observed by fluorescence microscopy examination. DTX-loaded PTNPs exhibited higher cytotoxicity than free DTX with a 3 to 4.4-fold decrease in drug dose required for 50% cell growth inhibition. The hydrophilic backbone of the amphiphilic polymer improved the fluidity of PTNPs which enhanced the longitudinal relaxivity (r1) of loaded MnO NPs by 2.7-fold with r1=2.4mM(-1)s(-1). Whole body fluorescence imaging (FI) and magnetic resonance imaging (MRI) showed significant accumulation and prolonged retention of PTNPs in orthotopic MDA-MB-231 breast tumors. These results suggest that the new amphiphilic polymer-based PTNP system, able to simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence, is a good candidate for cancer theranostic applications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A new multifunctional terpolymeric system for simultaneous imaging and drug delivery has been recently developed in our laboratory. Herein we report the investigation of terpolymeric contrast agent for magnetic resonance imaging and doxorubicin (Dox) delivery. The polymer was synthesized by graft polymerization of methacrylic acid (MAA) and polysorbate 80 (PS 80) onto starch with multiple, chemically bound diethylenetriaminepenta acetic acid (DTPA) groups for gadolinium chelating. The terpolymer self-assembled to form nanoparticles upon addition of doxorubicin which binds with the PMAA chain. The physicochemical, biological and pharmacokinetic properties of the polymeric system were characterized and their contrast enhancement capability was evaluated in vitro and in vivo. The polymer was able to load gadolinium with high thermodynamic stability and exhibited low cytotoxicity. The Gd-loaded polymer (PolyGd), and Gd-Dox co-loaded nanoparticles (PolyGd-Dox) significantly enhanced MR signals, with ionic T1 relaxivities 3-5 times higher than those from Omniscan®, a small molecule contrast agent. In vivo studies showed superior and prolonged contrast enhancement compared to Omniscan® at one fourth the equivalent dose, without adverse effects. The PolyGd and PolyGd-Dox accumulated in the tumor and painted the tumor boundaries clearly for at least 48h. The PolyGd also enhanced angiogram contrast with contrast to noise ratio values of up to 55-fold and a blood half-life time of 200min. Seven days after intravenous administration, only relatively small amounts of gadolinium could be detected in the major organs of the mice (supplementary materials). These results suggest that the new terpolymeric system is useful as a theranostic platform for contrast enhanced MR imaging of vasculature and tumor as well as Dox delivery., (Copyright © 2013 Elsevier B.V. All rights reserved.)

For effective and safe thermotherapy, real-time, accurate, three-dimensional tissue thermometry is required. Magnetic resonance imaging (MRI)-based thermometry in combination with current temperature responsive contrast agents only provides an 'off-on' signal at a certain temperature, not indicating temperature increases beyond the desired therapeutic levels. To overcome this limitation, a novel Gd-chelated hydrogel-lipid hybrid nanoparticle (HLN) formulation was developed that provides an 'off-on-off' signal defining a thermometric window for MR thermometry. Novel thermally responsive poly(N-isopropylacrylamide-co-acrylamide) (NIPAM-co-AM) hydrogel nanoparticles (<15 nm) with bisallylamidodiethylenetriaminetriacetic acid, a novel crosslinker with Gd(3+) chelation functionality, were synthesized. The Gd-hydrogel nanoparticles were encapsulated in a solid lipid nanoparticle matrix that prevented T(1)-weighted contrast signal enhancement. Melting of the matrix lipid freed the Gd-hydrogel nanoparticles into the bulk water and an 'off-on' contrast signal enhancement occurred. As the temperature was further increased to temperatures greater than, the volume phase transition temperature of the hydrogel nanoparticles, they collapsed and provided an 'on-off' signal diminution. Both the 'off-on' and the 'on-off' transition temperature could be tailored by changing the lipid matrix and altering the NIPAM/AM ratio in the hydrogel, respectively. This allowed MRI thermometry of different temperature windows using the Gd-HLN system., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This paper presents the first study of molecular interactions of ingredients and internal nanostructure in relation to drug loading and release mechanisms/kinetics of rationally designed solid polymer-lipid hybrid nanoparticles (PLN). The PLN were prepared by using a rationally selected composition that was found in our previous work to provide optimized interactions of verapamil hydrochloride (VRP) with dextran sulfate sodium (DS) and then the VRP-DS complex with dodecanoic acid (DA). The solid-state properties of the components, their molecular interactions and the morphology, particle size and internal structure of PLN were determined by use of differential scanning calorimetry, powder X-ray diffraction, (13)C nuclear magnetic resonance, Fourier transform infrared spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering. The distribution of VRP in PLN was examined by TEM imaging using a cationic gold tracer. Drug release studies were conducted in various media. Drug loading as high as 36% and loading efficiencies up to 99% were achieved in the rationally formulated PLN. Hydrogen bonding between drug, polymer and lipid and a uniform distribution of amorphous VRP within the solid lipid matrix were evident. Sustained drug release from the PLN was mainly controlled by ion exchange and diffusion processes. The results demonstrated that strong molecular interactions among the drug, the polymer and the lipid in the optimized formulation were responsible for the improved drug loading and release performance of the PLN.

Multidrug-resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize for the effectiveness of this combinational approach, novel polymer-lipid hybrid nanoparticle (PLN) formulations capable of delivering a cytotoxic drug, doxorubicin (Dox), a chemosensitizer, GG918, or their combination were prepared. Both acute and long-term anticancer activities of various combinations of Dox and GG918 in solution or PLN form were evaluated in a human MDR breast cancer cell line (MDA435/LCC6/MDR1) using trypan blue exclusion and clonogenic assays. Cellular Dox uptake and drug distribution within the cells were determined by fluoremetry and fluorescence microscopy. The results showed that the encapsulation efficiencies of Dox and GG918 in PLN were up to 89% and were not compromised by co-encapsulation of the two agents. Of various combinational treatment approaches, the Dox and GG918 co-encapsulated PLN formulation ((DG)n) demonstrated the greatest Dox uptake and anticancer activity to the MDR cells, while co-administration of two single-agent loaded PLN was least effective. Fluorescence microscopy indicated cellular internalization of (DG)n. These findings suggest that in addition to the total drug concentrations, the simultaneous delivery of Dox and GG918 to the same cellular location is critical in determining the therapeutic effectiveness of this anticancer drug-chemosensitizer combination.

The purpose of this work was to determine the in vivo release profile of doxorubicin (Dox) delivered locoregionally by dextran-based microspheres (MS) and to develop an in vitro method for predicting in vivo drug release from MS-- in vitro-in vivo correlation (IVIVC). For the determination of in vivo Dox release, drug-loaded MS were placed into hollow fibers (HF) and implanted subcutaneously into C3H mice. Samples were retrieved at various times following implantation, MS removed from HF, and the amount of Dox remaining determined via ultraviolet/visible (UV/Vis) spectrophotometry. Various in vitro systems were designed and investigated for their ability to link in vivo and in vitro release profiles, including an open system (e.g. a column) with continuous flow of release medium at different flow rates and closed systems (e.g. a cuvette) using different release media and conditions. About 34% of loaded Dox was released from MS in vivo at 48 h. Only an incremental release was observed over the ensuing 72 h. The release kinetics of Dox from MS using three of the investigated in vitro systems, column system and HF immersed in a buffer solution or growth medium gave release profiles that were highly correlated with the in vivo release profile (r(2)>0.9). The relationships, both linear and non-linear, suggest that Level A IVIVC models can be developed for Dox release from locoregionally delivered MS using specially designed release systems.

The objective of this study was to investigate various factors that influence doxorubicin (Dox) loading onto and release from sulfopropyl dextran ion-exchange microspheres (MS), and to evaluate the anticancer activity of the released drug in vitro. Dox was incorporated into the MS by incubating the MS with aqueous solutions of Dox at room temperature. The drug release was carried out at 37 degrees C in aqueous solutions containing NaCl with or without CaCl2. The kinetics of drug absorption and release, the amount of Dox released, and the stability of Dox after loading, freeze-drying, and release were determined by spectrophotometry. The cytotoxicity of Dox (the original drug or that released from MS) against murine EMT6 breast cancer cells was assessed using a clonogenic assay. An increase in the MS to drug ratio resulted in a higher absorption rate and a higher fraction of the drug extracted from the solution. The release rate and the equilibrium fraction of Dox released increased with a decrease in the initial amount of Dox loaded or an increase in the salt concentration. The addition of divalent ions (Ca2+) promoted drug release compared to NaCl alone. The percent loss of colony forming ability of the cells, a measure of cytotoxicity of the released Dox, was the same as parent Dox solutions, indicating that the drug bioactivity was fully preserved after the drug loading and release cycle. This work demonstrated that various drug release rates were achieved by varying the drug loading and that the MS-delivered Dox was effective against the cancer cells in vitro.