Lisa Brannon-Peppas

Active targeting schemes for nanoparticle systems in cancer therapeutics.

The objective of this review is to outline current major cancer targets for nanoparticle systems and give insight into the direction of the field. The major targeting strategies that have been used for the delivery of therapeutic or imaging agents to cancer have been broken into three sections. These sections are angiogenesis-associated targeting, targeting to uncontrolled cell proliferation markers, and tumor cell targeting. The targeting schemes explored for many of the reported nanoparticle systems suggest the great potential of targeted delivery to revolutionize cancer treatment.

Doxorubicin-loaded PLGA nanoparticles by nanoprecipitation: preparation, characterization and in vitro evaluation

AIMSnThe lack of specificity of chemotherapeutic agents to cancer tissue commonly leads to dose-limiting side effects and poor therapeutic results. Drug delivery systems promise to improve the deficiencies of chemotherapeutic treatment by modifying the biodistribution and pharmacokinetics of the drug in vivo. Here, we report the preparation, characterization and in vitro evaluation of a carrier for the chemotherapeutic drug doxorubicin based on acid-capped poly(lactic-co-glycolic acid) nanoparticles.nnnMETHODSnDoxorubicin-loaded nanoparticles were prepared by nanoprecipitation with bovine serum albumin as the stabilizer. Nanoparticles were characterized and their interaction with MDA-MB-231 breast cancer cells was examined with confocal microscopy and a toxicological assay.nnnRESULTSnSpherical particles with an average diameter of 230 nm, a zeta-potential of -45 mV and a maximum drug loading of 5 wt% were prepared. Doxorubicin was found to be quickly released at endolysosomal pH of 4.0 but was released at a slower rate at pH 7.4. Nanoparticles were found to deliver the drug into cells quickly and in higher quantity than when presented in solution and were found to result in a therapeutic efficacy comparable to the free drug.nnnDISCUSSIONnNanoprecipitation was found to be a promising method for the preparation of nanoparticles with relatively high doxorubicin loading. The pH-dependent release behavior is discussed to possibly be a result of accelerated degradation of the polymer and decreasing ionic interaction between the drug and the polymer at acidic pH. Additional studies are needed to determine why increased nuclear localization of the drug when delivered in the form of nanoparticles did not result in increased therapeutic efficacy in vitro.nnnCONCLUSIONnNanoparticles formulated by nanoprecipitation of acid-ended poly(lactic-co-glycolic acid) were found to be able to control the release of doxorubicin in a pH-dependent manner and to effectively deliver high payloads of the drug in an active form to MDA-MB-231 breast cancer cells.

PEGylation strategies for active targeting of PLA/PLGA nanoparticles

This work evaluates various techniques for the incorporation of poly(ethylene glycol) (PEG) onto biodegradable nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) (PLA) with the purpose of providing a functional site for surface conjugation of targeting agents and for improving surface properties. The techniques compared were based on NP preparation with blends of PLGA and poloxamer or with block copolymers of PLGA/PLA with PEG. Blending of PLGA with poloxamer 407 resulted in the incorporation of the latter to up to a 43 wt % content. Direct conjugation of heterofunctional NH2-PEG-COOH to the surface of premade NPs was not highly effective. Preparation of copolymers of PLGA with PEG was determined to be more effective and versatile by polymerization of lactide and glycolide dimers onto the hydroxyl group of heterofunctional OH-PEG-COOH than by conjugation of the premade polymers with carbodiimide chemistry. NPs prepared with these copolymers confirmed the surface localization of PEG and proved to be useful for conjugation of mouse immumoglobulin as a model targeting agent.

Novel vaginal drug release applications

Abstract A review is presented of types of vaginal drug delivery systems, both in commercial use and in research. The few delivery systems that do exist are usually used for contraception or to treat vaginal infections. Commercially available vaginal ring delivery systems are usually based upon silicone elastomers while pessaries (tablets or suppositories) are usually dissolving systems utilizing a variety of materials. The future of vaginal drug delivery lies in the bioadhesive tablets and microparticles which, although relatively new, show great promise in providing truly controlled delivery for more than just the few hours that current formulations can offer. The use of hydrogels such as poly(acrylic acid) and celluloses in these systems is critical because it supplies the bioadhesive nature of the formulations.

Poly(Lactic-co-Glycolic) Acid as a Carrier for Imaging Contrast Agents

PurposeWith the broadening field of nanomedicine poised for future molecular level therapeutics, nano- and microparticles intended for the augmentation of either single- or multimodal imaging are created with PLGA as the chief constituent and carrier.MethodsEmulsion techniques were used to encapsulate hydrophilic and hydrophobic imaging contrast agents in PLGA particles. The imaging contrast properties of these PLGA particles were further enhanced by reducing silver onto the PLGA surface, creating a silver cage around the polymeric core.ResultsThe MRI contrast agent Gd-DTPA and the exogenous dye rhodamine 6G were both encapsulated in PLGA and shown to enhance MR and fluorescence contrast, respectively. The silver nanocage built around PLGA nanoparticles exhibited strong near infrared light absorbance properties, making it a suitable contrast agent for optical imaging strategies such as photoacoustic imaging.ConclusionsThe biodegradable polymer PLGA is an extremely versatile nano- and micro-carrier for several imaging contrast agents with the possibility of targeting diseased states at a molecular level.

Preparation and initial characterization of biodegradable particles containing gadolinium-DTPA contrast agent for enhanced MRI

Accurate imaging of atherosclerosis is a growing necessity for timely treatment of the disease. Magnetic resonance imaging (MRI) is a promising technique for plaque imaging. The goal of this study was to create polymeric particles of a small size with high loading of diethylenetriaminepentaacetic acid gadolinium (III) (Gd-DTPA) and demonstrate their usefulness for MRI. A water-in-oil-in-oil double emulsion solvent evaporation technique was used to encapsulate the MRI agent in a poly(lactide-co-glycolide) (PLGA) or polylactide-poly(ethylene glycol) (PLA-PEG) particle for the purpose of concentrating the agent at an imaging site. PLGA particles with two separate average sizes of 1.83 μm and 920 nm, and PLA-PEG particles with a mean diameter of 952 nm were created. Loading of up to 30 wt % Gd-DTPA was achieved, and in vitro release occurred over 5 h. PLGA particles had highly negative zeta potentials, whereas the particles incorporating PEG had zeta potentials closer to neutral. Cytotoxicity of the particles on human umbilical vein endothelial cells (HUVEC) was shown to be minimal. The ability of the polymeric contrast agent formulation to create contrast was similar to that of Gd-DTPA alone. These results demonstrate the possible utility of the contrast agent-loaded polymeric particles for plaque detection with MRI.

Silver nanosystems for photoacoustic imaging and image-guided therapy

Due to their optical absorption properties, metallic nanoparticles are excellent photoacoustic imaging contrast agents. A silver nanosystem is presented here as a potential contrast agent for photoacoustic imaging and image-guided therapy. Currently, the nanosystem consists of a porous silver layer deposited on the surface of spherical silica cores ranging in diameter from 180 to 520 nm. The porous nature of the silver layer will allow for release of drugs or other therapeutic agents encapsulated in the core in future applications. In their current PEGylated form, the silver nanosystem is shown to be nontoxic in vitro at concentrations of silver up to 2 mgml. Furthermore, the near-infrared absorbance properties of the nanosystem are demonstrated by measuring strong, concentration-dependent photoacoustic signal from the silver nanosystem embedded in an ex vivo tissue sample. Our study suggests that silver nanosystems can be used as multifunctional agents capable of augmenting image-guided therapy techniques.

Encapsulation of nucleic acids and opportunities for cancer treatment.

The development of nucleic acid drugs for the treatment of various cancers has shown great promise in recent years. However, efficient delivery of these drugs to target cells remains a significant challenge towards the successful development of such therapies. This review provides a comprehensive overview of encapsulation technologies being developed for the delivery of nucleic acid-based anti-cancer agents. Both micro and nanoparticles systems are discussed along with their use in delivering plasmid DNA as well as oligonucleotides. The majority of the systems discussed have used DNA immunotherapy as the potential mode of anticancer therapy, which requires targeting to antigen presenting cells. Other applications, including those with oligonucleotides, focus on targeting tumor cells directly. The results obtained so far show the excellent promise of encapsulation as an efficient means of delivering therapeutic nucleic acids.

Rhodamine-loaded poly(lactic-co-glycolic acid) nanoparticles for investigation of in vitro interactions with breast cancer cells.

Nanoparticle-based drug delivery systems are considered promising for the delivery of imaging agents and drugs for the detection and treatment of illnesses, including cancer. Investigation of nanoparticle interactions with the diseased cells can lead to better designs. In this work, poly(lactic-co-glycolic acid) nanoparticles loaded with rhodamine 6G were prepared by nanoprecipitation with high encapsulation efficiency. In vitro release studies demonstrated that rhodamine escaped from the nanoparticles at a very slow rate at physiological pH, thus making it ideal for imaging studies. At acidic pH this agent was released quickly, suggesting charge interactions between the polymer and rhodamine. Microscopy and flow cytometry studies show higher uptake in MDA-MB-231 breast cancer cells when exposed to rhodamine-loaded nanoparticles than to rhodamine in solution.

Combined ultrasound and photoacoustic imaging of pancreatic cancer using nanocage contrast agents

A new metallodielectric nanoparticle consisting of a silica core and silver outer cage was developed for the purpose of enhancing photoacoustic imaging contrast in pancreatic tissue. These nanocages were injected into an ex vivo porcine pancreas and imaged using a combined photoacoustic and ultrasound (PAUS) assembly. This custom-designed PAUS assembly delivered 800 nm light through a fiber optical light delivery system integrated with 128 element linear array transducer operating at 7.5 MHz center frequency. Imaging results prove that the nanocage contrast agents have the ability to enhance photoacoustic imaging contrast. Furthermore, the value of the combined PAUS imaging modality was demonstrated as the location of nanocages against background native tissue was evident. Future applications of these nanocage contrast agents could include targeting them to pancreatic cancer for enhancement of photoacoustic imaging for diagnosis and therapy.