Benjamin A. Teply

Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers

There has been progressively heightened interest in the development of targeted nanoparticles (NPs) for differential delivery and controlled release of drugs. Despite nearly three decades of research, approaches to reproducibly formulate targeted NPs with the optimal biophysicochemical properties have remained elusive. A central challenge has been defining the optimal interplay of parameters that confer molecular targeting, immune evasion, and drug release to overcome the physiological barriers in vivo. Here, we report a strategy for narrowly changing the biophysicochemical properties of NPs in a reproducible manner, thereby enabling systematic screening of optimally formulated drug-encapsulated targeted NPs. NPs were formulated by the self-assembly of an amphiphilic triblock copolymer composed of end-to-end linkage of poly(lactic-co-glycolic-acid) (PLGA), polyethyleneglycol (PEG), and the A10 aptamer (Apt), which binds to the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer (PCa) cells, enabling, respectively, controlled drug release, “stealth” properties for immune evasion, and cell-specific targeting. Fine-tuning of NP size and drug release kinetics was further accomplished by controlling the copolymer composition. By using distinct ratios of PLGA-b-PEG-b-Apt triblock copolymer with PLGA-b-PEG diblock copolymer lacking the A10 Apt, we developed a series of targeted NPs with increasing Apt densities that inversely affected the amount of PEG exposure on NP surface and identified the narrow range of Apt density when the NPs were maximally targeted and maximally stealth, resulting in most efficient PCa cell uptake in vitro and in vivo. This approach may contribute to further development of targeted NPs as highly selective and effective therapeutic modalities.

Nanoparticle-aptamer bioconjugates for targeted antineoplastic drug delivery

Targeted drug delivery technologies can provide physicians with new approaches to treat and manage patients with cancer. Nucleic acid ligands (aptamers) are a novel class of targeting molecules that can be used in a similar manner to antibodies. Beyond use as drugs themselves, aptamers have the potential to serve as targeting ligands to deliver drugs, imaging agents, or other bioactive agents to the intended site of action. Bioconjugates of nanoparticles and aptamers can selectively bind and be taken up by cancer cells. In this article we review progress to date for antineoplastic drug delivery using nanoparticle-aptamer bioconjugates.Aptamers are isolated through a process of in vitro selection, also referred to as systematic evolution of ligands by exponential enrichment (SELEX). There is an increasing numbers of aptamers for cancer targeting being reported in the literature. These aptamers often interact with antigens that are overexpressed exclusively, or preferentially, on cancer cells or in the cancer microenvironment. As novel drug delivery vehicles, nanoparticle-aptamer bioconjugates may be developed to target a myriad of diseases including many cancers by delivering a variety of therapeutic agents specifically to the site of interest.The first in vivo study of antineoplastic drug delivery by a bioconjugate employed nanoparticle encapsulating docetaxel and aptamers that bind certain prostate cancer cells. In this study using a xenograft murine model of prostate cancer, these bioconjugates were shown to significantly improve tumor reduction after intratumoral injection compared with all controls. Furthermore, the docetaxel-loaded nanoparticle-aptamer bioconjugates demonstrated reduced toxicity in terms of acute bodyweight loss compared with the controls. In vitro, the efficacy of the docetaxel-loaded nanoparticle-aptamer bioconjugate was shown to be due to intracellular delivery of the drug to the cancer cells, and the bioconjugate without the drug had no cytotoxicity.Nanoparticle-aptamer bioconjugates may prove to be useful not only for management of cancer but also various other indications. New aptamers, multivalent targeting strategies, and multimodal treatments such as simultaneous radio- and chemotherapy may further increase the efficacy of these bioconjugates and facilitate their clinical translation for therapeutic and diagnostic applications.

Magnetite-PLGA Microparticles for Oral Delivery of Insulin

Magnetic responsive particles were designed for use in oral delivery of insulin. Magnetite nanoparticles (12 nm average size) were synthesized and co-encapsulated with insulin into poly(lactide-co-glycolide) (PLGA) microparticles (4.6 ± 2.2 µm average particle size) through the double-emulsion method. The spherical structures of resulting microparticles were well maintained at magnetite content 5 wt % or less. Mice were gavaged with 125 I-insulin-magnetitePLGA microparticles and a circumferential trans-abdominal magnetic field was applied forty minutes after administration to retard the transit of the microparticles in the intestinal tract. As control, mice were similarly dosed without the subsequent trans-abdominal magnetic field. Mice were sacrificed, and the intestinal radioactivity was 101% and 145% higher in treated mice versus the control at 6 h and 12 h, respectively. A single administration of 50 unit/kg Humulin Rmagnetite-PLGA microparticles to the fasted mice resulted in 66% reduction of blood glucose level in the presence of external magnetic field at 12 h, compared to 27% reduction in the absence of magnetic field.