Frank Alexis

Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform.

We report the engineering of a novel lipid-polymer hybrid nanoparticle (NP) as a robust drug delivery platform, with high drug encapsulation yield, tunable and sustained drug release profile, excellent serum stability, and potential for differential targeting of cells or tissues. The NP comprises three distinct functional components: (i) a hydrophobic polymeric core where poorly water-soluble drugs can be encapsulated; (ii) a hydrophilic polymeric shell with antibiofouling properties to enhance NP stability and systemic circulation half-life; and (iii) a lipid monolayer at the interface of the core and the shell that acts as a molecular fence to promote drug retention inside the polymeric core, thereby enhancing drug encapsulation efficiency, increasing drug loading yield, and controlling drug release. The NP is prepared by self-assembly through a single-step nanoprecipitation method in a reproducible and predictable manner, making it potentially suitable for scale-up.

Targeted nanoparticles for cancer therapy

Over the past decade, there has been an increasing interest in using nanotechnology for cancer therapy. The development of smart targeted nanoparticles (NPs) that can deliver drugs at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating primary and advanced metastatic tumors. We highlight some of the promising classes of targeting molecules that are under development for the delivery of NPs. We also review the emerging technologies for the fabrication of targeted NPs using microfluidic devices.

Superparamagnetic Iron Oxide Nanoparticle–Aptamer Bioconjugates for Combined Prostate Cancer Imaging and Therapy

ThemajorshortcomingofCombidexisitsinabilitytodetectPCadiseaseoutsideofthelymphnodes.Herein, we report the development of a novel, multifunc-tional, thermally cross-linked SPION (TCL-SPION) that can bothdetect PCa cells, and deliver targeted chemotherapeuticagents directly to the PCa cells. We previously reported theuseoftheA10RNAaptamer (Apt), which bindstheextracellu-lar domain of the prostate-specific membrane antigen (PSMA),to engineer targeted nanoparticles for PCa therapy and imag-ing.

Nanoparticle technologies for cancer therapy.

Nanoparticles as drug delivery systems enable unique approaches for cancer treatment. Over the last two decades, a large number of nanoparticle delivery systems have been developed for cancer therapy, including organic and inorganic materials. Many liposomal, polymer-drug conjugates, and micellar formulations are part of the state of the art in the clinics, and an even greater number of nanoparticle platforms are currently in the preclinical stages of development. More recently developed nanoparticles are demonstrating the potential sophistication of these delivery systems by incorporating multifunctional capabilities and targeting strategies in an effort to increase the efficacy of these systems against the most difficult cancer challenges, including drug resistance and metastatic disease. In this chapter, we will review the available preclinical and clinical nanoparticle technology platforms and their impact for cancer therapy.

New frontiers in nanotechnology for cancer treatment

Nanotechnology is a field of research at the crossroads of biology, chemistry, physics, engineering, and medicine. Design of multifunctional nanoparticles capable of targeting cancer cells, delivering and releasing drugs in a regulated manner, and detecting cancer cells with enormous specificity and sensitivity are just some examples of the potential application of nanotechnology to oncological diseases. In this review we discuss the recent advances of cancer nanotechnology with particular attention to nanoparticle systems that are in clinical practice or in various stages of development for cancer imaging and therapy.

Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates.

Apromisingapplicationofnanoparticle(NP)drugdeliverysystemsisthetargeteddeliveryoftherapeuticagentsinacell-,tissue-,ordisease-specificmanner.Thisgoalmaybeachieved by the surface-modification of NPs with antibodies,nucleic acid ligands (aptamers; Apt), peptides, or small mole-cules that bind to antigens present on the target cells or tis-sues.

Stimulus responsive nanogels for drug delivery

Stimulus responsive nanogels are polymeric nanoparticles which are capable of responding to external stimuli by changing their physico-chemical properties, such as volume, water content, refractive index, permeability, and hydrophilicity–hydrophobicity. Compared with other polymer nanoparticles used for drug delivery, stimulus responsive nanogels are noted for their ability to encapsulate bioactive drugs, their high stability for prolonged circulation in the blood stream, and their controlled release and site-specific targeting of loaded drugs modulated by environment stimuli. Particularly, the application of stimulus responsive nanogels provides an interesting opportunity for drug delivery in which the delivery system becomes an active participant, rather than a passive carrier, in the optimization of disease therapy. In this article, the authors review the recent developments in the preparation and application in drug delivery of stimulus responsive nanogels which can respond to small temperature and pH changes, light, magnetic field, biomolecule recognition (specifically glucose responsive nanogels for insulin delivery), and multi-responsive nanogels. The limitations and future improvements of stimulus responsive nanogels are also discussed.

Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery

Nanoparticles targeted to the neonatal Fc receptor cross the intestinal epithelium and reach systemic circulation after oral administration. A Spoonful of Nanomedicine Oral delivery of drug-loaded nanoparticles is, to some, the Holy Grail of nanomedicine. Patients can easily pop a pill, which makes them more compliant with a therapeutic regimen. The difficulty with ingesting these tiny particles is that they are not readily absorbed in the intestine, thus eliminating most of the particles from the body and, in turn, limiting efficacy. In response, Pridgen et al. designed polymeric nanoparticles targeting a receptor expressed on the surface of the intestine to actively transport the particle across the cell into the patient’s circulation. The nanoparticles were decorated with Fc fragments that readily bind to the neonatal Fc receptor (FcRn) in the intestinal epithelium. The authors observed that the Fc-targeted nanoparticles crossed the intestinal barrier both in vitro, using human epithelial cells, and in vivo in mice (who also express FcRn), ending up in high concentrations in several organs of the body. By contrast, nontargeted nanoparticles were barely visible. To demonstrate the therapeutic benefits of these Fc-targeted nanoparticles, Pridgen et al. administered insulin-laden targeted and nontargeted particles orally to mice. Free insulin given orally did not generate a glucose response in the animals, similar to the nontargeted, insulin-containing particles. However, Fc-targeted nanoparticles containing insulin produced a significant hypoglycemic response in the mice. To confirm that the targeting and epithelial transport is important for this mode of delivery, the authors showed that animals lacking FcRn did not respond to the insulin-filled Fc-targeted nanoparticles. The ability to deliver nanomedicine orally would open doors to treating many chronic diseases that require daily therapy, such as diabetes and cancer. This study by Pridgen et al. is an exciting proof of concept but will require longer periods of testing in disease models to confirm that FcRn targeting is essential and safe for human use. Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration.

HER-2-targeted nanoparticle-affibody bioconjugates for cancer therapy.

Affibodies are a class of polypeptide ligands that are potential candidates for cell- or tissue-specific targeting of drug-encapsulated controlled release polymeric nanoparticles (NPs). Here we report the development of drug delivery vehicles comprised of polymeric NPs that are surface modified with Affibody ligands that bind to the extracellular domain of the trans-membrane human epidermal growth factor receptor 2 (HER-2) for targeted delivery to cells which over express the HER-2 antigen. NPs lacking the anti-HER-2 Affibody did not show significant uptake by these cells. Using paclitaxel encapsulated NP-Affibody (1 wt% drug loading), we demonstrated increased cytotoxicity of these bioconjugates in SK-BR-3 and SKOV-3 cell lines. These targeted, drug encapsulated NPAffibody bioconjugates may be efficacious in treating HER-2 expressing carcinoma.

Synthesis of Brightly PEGylated Luminescent Magnetic Upconversion Nanophosphors for Deep Tissue and Dual MRI Imaging

A method is developed to fabricate monodispersed biocompatible Yb/Er or Yb/Tm doped β-NaGdF4 upconversion phosphors using polyelectrolytes to prevent irreversible particle aggregation during conversion of the precursor, Gd2 O(CO3 )2.H2 O:Yb/Er or Yb/Tm, to β-NaGdF4 :Yb/Er or Yb/Tm. The polyelectrolyte on the outer surface of nanophosphors also provided an amine tag for PEGylation. This method is also employed to fabricate PEGylated magnetic upconversion phosphors with Fe3 O4 as the core and β-NaGdF4 as a shell. These magnetic upconversion nanophosphors have relatively high saturation magnetization (7.0 emu g(-1) ) and magnetic susceptibility (1.7 × 10(-2) emu g(-1) Oe(-1) ), providing them with large magnetophoretic mobilities. The magnetic properties for separation and controlled release in flow, their optical properties for cell labeling, deep tissue imaging, and their T1 - and T2 -weighted magnetic resonance imaging (MRI) relaxivities are studied. The magnetic upconversion phosphors display both strong magnetophoresis, dual MRI imaging (r1 = 2.9 mM(-1) s(-1) , r2 = 204 mM(-1) s(-1) ), and bright luminescence under 1 cm chicken breast tissue.