Synthetic Drug Delivery Research Articles

Abstract B59: Enhancing T-cell therapy through TCR signaling-responsive nanogel drug delivery

Abstract Adoptive cell transfer (ACT) with autologous tumor-reactive T-cells has recently shown great promise in the treatment of leukemia in clinical trials. Effective control of solid tumors, remain challenging. Glioblatoma multiforme (GM) is a lethal disease in need of clinically effective therapies. Ninety-seven percent of tumors in the ‘classical’ subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of EGFR. In the present study we utilize a novel carrier-free delivery strategy to specifically support a EGFR directed chimeric antigen receptor (CAR) T-cell with recombinant Interleukin-15 super agonist (IL15-Sa), in a heterotopic mouse model of GM. CAR-T cell design: The CAR-T cell was designed based on the heavy and light chains of cetuximab to form a single-chain variable fragment, which was fused to a portion of the extracellular and transmembrane domains of human CD8 alpha, followed by the intracellular domains of 4-1BB and CD3 zeta. The bicistronic vector also encoded truncated human CD19 as a selectable marker. The plasmid coding hu EGFRscFv-BBz-CAR was synthesized and lentivirus packaging was made. Isolated T cells were derived from leukapheresis products and stimulated with Dynabeads Human T Activator CD3/CD28. T cell were cultured and were transduced and or left untransduced one day following bead stimulation, and then T cells were expanded for 10 days and cryopreserved. Surface expression of the CAR was confirmed and quantified with biotinylated human EGFR protein and by staining for CD19. CAR-T cells phenotype was identified. Coupling of NGs to T cells: anti CD45 antibody (aCD45) against highly expressed cell surface phosphatase CD45 was used as an anchor to stably link human IL-15Sa as a drug cargo/nanogel (NG) to the T cell surface. The aCD45/IL-15-Sa-NG was added to CAR T cells. In vivo therapy study using human Chimeric Antigen Receptor (CAR)-T cells: Luciferase-expressing U-87 MG human glioblastoma cells (1.0 × 106) were injected s.c. into NSG mice on Day 0. Animals received i.v. adoptive transfer of activated CAR-T cells (2.6×106 total T-cells -38% transduction equating to 106 CAR-T-cells)) alone or with surface coupled NGs on Day 7. In other groups, free IL-15Sa was injected i.v. after ACT at equivalent dose. Tumor area and body weight were measured every two days. Mice were also imaged for bioluminescence to monitor the tumor growth and were euthanized when body weight loss was beyond 20%, or tumor area reached 150 mm2 or the animal had become moribund. Findings: CAR T-cells backpacked with IL-15Sa-NGs were compared to CAR T-cells alone or T-cells supplemented with an equivalent systemic dose of free IL-15Sa. NG-backpacked CAR T-cells eradicated tumors in 80% of animals. By contrast, transfer of CAR-T cells alone had a small impact on tumor growth and survival, which did not reach statistical significance; responses were marginally improved by the addition of free IL-15Sa. We have demonstrated NG delivery of cytokines has the potential to enhance CAR T-cell therapy in a mice model of GM. This strategy should be broadly applicable in ACT strategies employing natural, TCR-engineered, or CAR T-cell therapies, and illustrates a general approach to couple the action of a synthetic drug delivery carrier to the function of therapeutic cells. Citation Format: Ana Castano, Li Tang, Sagar Kudchodkar, Irvine Darrell, Marcela Maus. Enhancing T-cell therapy through TCR signaling-responsive nanogel drug delivery. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B59.

Remotely controlled red blood cell carriers for cancer targeting and near-infrared light-triggered drug release in combined photothermal chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus-responsive, RBC-based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus‐responsive, RBC‐based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near‐infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light‐induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC‐based cancer cell targeted drug delivery and light‐controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.

Exosomes: potential model for complement-stealth delivery systems

AbstractExosomes are nature’s nanocarriers that transport biological information in humans. Their structural properties, origin and functions are making them interesting objects for the diagnosis of diseases, such as cancer, and also, as innovative tools for drug delivery. The interaction of exosomes with the immune system has been one of the focal points of interest; nevertheless their “stealth” properties helping to avoid adverse immune reactions are still not fully understood. In this review, after giving an overview of recent findings on the role of exosomes in disease pathogenesis and physiological functions, we focused on their interaction with the immune system and possibilities for clinical applications. The potential of exosomes of creating stealth nanoparticles that are better tolerated by the immune system than the presently available synthetic drug delivery systems represent a promising new approach in nanomedicine.

Physico-chemical characterization of polymeric micelles loaded with platinum derivatives by capillary electrophoresis and related methods

(1,2-diamino-cyclohexane)Platinum(II) ((DACH)Pt) loaded polymeric micelles of poly(ethylene glycol-b-sodium glutamate) (PEG-b-PGlu) are currently studied as a potential candidate to replace oxaliplatin in the treatment of cancers with the aim to reduce side effects like cumulative peripheral distal neurotoxicity and acute dysesthesias. As for all synthetic polymeric drug delivery systems, the characterization of the (co)polymer precursors and of the final drug delivery system (polymeric micelles) is crucial to control the repeatability of the different batches and to get correlation between physico-chemical structure and biological activity. In this work, the use of capillary electrophoresis (CE) and related methods for the characterization of (DACH)Pt-loaded polymeric micelles and their precursor (PEG-b-PGlu copolymer) has been investigated in detail. The separation and quantification of residual PGlu homopolymer in the PEG-b-PGlu sample were performed by free solution capillary zone electrophoresis mode. This mode brought also information on the PEG-b-PGlu copolymer composition and polydispersity. It also permitted to monitor the decomposition of polymeric micelles in the presence of NaCl at room temperature. Interactions between PEG-b-PGlu unimers, on one hand, and polymeric micelles or surfactants, on the other hand, were studied by using the Micellar Electrokinetic Chromatography and Frontal Analysis Capillary Electrophoresis modes. Finally, weight-average hydrodynamic radii of the loaded polymeric micelles and of the PEG-b-PGlu unimers were determined by Taylor Dispersion Analysis (an absolute size determination method that can be easily implemented on CE apparatus).

Advancing stem cell therapy from bench to bedside: lessons from drug therapies.

The inadequacy of existing therapeutic tools together with the paucity of organ donors have always led medical researchers to innovate the current treatment methods or to discover new ways to cure disease. Emergence of cell-based therapies has provided a new framework through which it has given the human world a new hope. Though relatively a new concept, the pace of advancement clearly reveals the significant role that stem cells will ultimately play in the near future. However, there are numerous uncertainties that are prevailing against the present setting of clinical trials related to stem cells: like the best route of cell administration, appropriate dosage, duration and several other applications. A better knowledge of these factors can substantially improve the effectiveness of disease cure or organ repair using this latest therapeutic tool. From a certain perspective, it could be argued that by considering certain proven clinical concepts and experience from synthetic drug system, we could improve the overall efficacy of cell-based therapies. In the past, studies on synthetic drug therapies and their clinical trials have shown that all the aforementioned factors have critical ascendancy over its therapeutic outcomes. Therefore, based on the knowledge gained from synthetic drug delivery systems, we hypothesize that by employing many of the clinical approaches from synthetic drug therapies to this new regenerative therapeutic tool, the efficacy of stem cell-based therapies can also be improved.

Self-assembled rosette nanotubes encapsulate and slowly release dexamethasone

Rosette nanotubes (RNTs) are novel, self-assembled, biomimetic, synthetic drug delivery materials suitable for numerous medical applications. Because of their amphiphilic character and hollow architecture, RNTs can be used to encapsulate and deliver hydrophobic drugs otherwise difficult to deliver in biological systems. Another advantage of using RNTs for drug delivery is their biocompatibility, low cytotoxicity, and their ability to engender a favorable, biologically-inspired environment for cell adhesion and growth. In this study, a method to incorporate dexamethasone (DEX, an inflammatory and a bone growth promoting steroid) into RNTs was developed. The drug-loaded RNTs were characterized using diffusion ordered nuclear magnetic resonance spectroscopy (DOSY NMR) and UV-Vis spectroscopy. Results showed for the first time that DEX can be easily and quickly encapsulated into RNTs and released to promote osteoblast (bone-forming cell) functions over long periods of time. As a result, RNTs are presented as a novel material for the targeted delivery of hydrophobic drugs otherwise difficult to deliver.

Red blood cell-mimicking synthetic biomaterial particles

Biomaterials form the basis of current and future biomedical technologies. They are routinely used to design therapeutic carriers, such as nanoparticles, for applications in drug delivery. Current strategies for synthesizing drug delivery carriers are based either on discovery of materials or development of fabrication methods. While synthetic carriers have brought upon numerous advances in drug delivery, they fail to match the sophistication exhibited by innate biological entities. In particular, red blood cells (RBCs), the most ubiquitous cell type in the human blood, constitute highly specialized entities with unique shape, size, mechanical flexibility, and material composition, all of which are optimized for extraordinary biological performance. Inspired by this natural example, we synthesized particles that mimic the key structural and functional features of RBCs. Similar to their natural counterparts, RBC-mimicking particles described here possess the ability to carry oxygen and flow through capillaries smaller than their own diameter. Further, they can also encapsulate drugs and imaging agents. These particles provide a paradigm for the design of drug delivery and imaging carriers, because they combine the functionality of natural RBCs with the broad applicability and versatility of synthetic drug delivery particles.

Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier

Protective mucus coatings typically trap and rapidly remove foreign particles from the eyes, gastrointestinal tract, airways, nasopharynx, and female reproductive tract, thereby strongly limiting opportunities for controlled drug delivery at mucosal surfaces. No synthetic drug delivery system composed of biodegradable polymers has been shown to penetrate highly viscoelastic human mucus, such as non-ovulatory cervicovaginal mucus, at a significant rate. We prepared nanoparticles composed of a biodegradable diblock copolymer of poly(sebacic acid) and poly(ethylene glycol) (PSA-PEG), both of which are routinely used in humans. In fresh undiluted human cervicovaginal mucus (CVM), which has a bulk viscosity approximately 1,800-fold higher than water at low shear, PSA-PEG nanoparticles diffused at an average speed only 12-fold lower than the same particles in pure water. In contrast, similarly sized biodegradable nanoparticles composed of PSA or poly(lactic-co-glycolic acid) (PLGA) diffused at least 3,300-fold slower in CVM than in water. PSA-PEG particles also rapidly penetrated sputum expectorated from the lungs of patients with cystic fibrosis, a disease characterized by hyperviscoelastic mucus secretions. Rapid nanoparticle transport in mucus is made possible by the efficient partitioning of PEG to the particle surface during formulation. Biodegradable polymeric nanoparticles capable of overcoming human mucus barriers and providing sustained drug release open significant opportunities for improved drug and gene delivery at mucosal surfaces.

Metal-Containing Proteins, Macrocycles, and Coordination Complexes in Therapeutic Applications and Disease

Treatment of diseases with natural and synthetic materials has been an aspiration of mankind since the dawn of human development. From the use of willow-bark to the marketing of aspirin, a steady move from folk remedies to the use of chemistry and biology to develop new therapies has been observed. In terms of metal-containing drugs, the platinum-containing drug cisplatin has long been the most effective metal-containing anticancer drug on the market. However, severe side effects of conventional drugs are associated with the inability to distinguish between healthy and cancer cells. Hence, a concerted world-wide effort is in progress to discover and characterise new drugs that may distinguish between healthy and cancer or other diseased cells. New techniques of drug delivery are sought and the use of natural products, proteins, antibodies, and synthetic polymers as drug delivery devices capable of targeting a diseased site is being investigated. These issues are nicely illustrated by macrocycles such as porphyrins, phthalocyanines, and related systems. Some of these compounds exhibit selective absorption by cancer cells and have the ability to photosensitize formation of singlet oxygen. These attributes have led to the development of alternative cancer treatments known as photodynamic therapy. Sadly, many potentially good new therapeutic agents often never leave the designers' laboratory due to some pharmacological problems associated with its in vivo use. The use of drug delivering devices, including water-soluble synthetic polymeric drug delivery systems, may help overcome many pharmacological drug-related problems, including those of solubility, specificity, and biocompatibility, factors that currently prevent many potentially good therapeutic agents from reaching clinics. The focus of this special issue is the synthesis, characterisation, physical studies, and application of synthetic metal-containing complexes and natural occurring proteins in serious human diseases such as cancer, diabetes, arthritis, viral disease, malaria, and tuberculosis with special focus on the following: porphyrins, phthalocyanines, and related complexes in photodynamic cancer therapy; proteins, enzymes, and synthetic polymeric drug delivery systems in the treatment of cancer and other diseases; coordination and organometallic compounds in cancer, arthritis, malaria, and viral disease. Towards these goals, L. Josefsen and R. Boyle describe in their review article the development and application of metal-based photosensitisers, including porphyrins and phthalocyanines, in photodynamic therapy. Four other publications highlight different aspects of porphyrin-based macrocyclic photosensitisers. S. Lee et al. focus on the cellular uptake and toxicity of thiotetra (ethylene glycol) monomethyl ether-functionalized porphyrazines. J.-Y. Liu et al. focus on in vitro photodynamic activity of novel amphiphilic zinc(II) phthalocyanines bearing oxyethylene-rich substituents. E. Antunes and T. Nyokong highlight the syntheses and photophysical properties of tetraazatetrabenzcorrole photosensitizers. Sakamoto et al. present a fundamental study of zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido)porphyrazine for application in photodynamic therapy of cancer. Considering polymeric drug delivery systems, South African E. Neuse's excellent review describes the use of synthetic polymers as metal-containing drug delivery vehicles in medicine. M. David Maree et al. provided a fine treatise on why biocompatible synthetic polymeric drug delivery systems are becoming increasing popular as drug delivering devices. They also demonstrate the principles behind these systems in a practical study utilising ferrocene and phthalocyanine derivatives anchored on a water-soluble polymeric drug carrier derived from lysine and aspartic acid. Italians Longo and Vasapollo demonstrated the use of phthalocyanine-based molecularly imprinted polymers as nucleoside receptors. X. Sun et al. report on the identification of proteins related to nickel homeostasis in Helicobater pylori by immobilized metal affinity chromatography and two-dimensional gel electrophoresis. P. Nagababu reported DNA-binding and photocleavage studies of cobalt (III) ethylenediamine pyridine complexes. M. Blackie and K. Chibale's excellent minireview focuses on metallocene antimalarials. The development of new metal-containing chemotherapeutic drugs is highlighted by contributions from M. Hogan et al. in their synthetic and cytotoxic study of new titanocene analogous. S. Mahepal et al. look at the in vitro antitumor activity of novel, mitochondrial-interactive, gold-based lipophilic cations. Sathisha et al. describe bis-isatin thiocarbohydrazone metal complexes and their antitumor activity against Ehrlich Ascites Carcinoma in Swiss albino mice. In conclusion, J. M. Botha and A. Roodt report mechanistic studies on trans-aquatetracyanooxo complexes of Re(V) and Tc(V) and discuss the implications of their results for nuclear medicine. We hope that this special issue will stimulate new research in all areas of metal-containing drug research and that it will help to focus research efforts of new and experienced researchers on key problems in the exciting field of metal-containing drug research. Jannie C. Swarts Michael J. Cook Edward N. Baker

Recent research and development in synthetic polymer-based drug delivery systems

In recent years, there has been increasing recognition that a number of synthetic polymers which have excellent biodegradability and biocompatibility are materials of pharmaceutical importance in the area of drug delivery technology. The aim of this review is to take a closer look at a few synthetic polymer-based drug delivery systems, specially the aliphatic polyesters, polyamides, polyethers, polyorthoesters, polyanhydrides, polyurethanes, hydrogels and dendritic polymers.

Carbohydrate-based templates for synthetic vaccines and drug delivery

Methyl tetra- O-allyl, and tetra- O-[2-(tetrahydro-2 H-pyranyl)oxy.-3-oxapentyl glucosides, and tetra- O-(cyanoethyl)galactosyl azide were converted into derivatives containing linkers with terminal carboxylic acid functionalities at the anomeric position and bearing four arms with phthaloyl- or BOC-protected terminal amino groups. These molecules were suitable for use in solid-phase peptide synthesis and for the preparation of dendrimers containing multiple copies of peptides.

The value and use of different contraceptive methods*

Reductions in the rates of maternal and child mortality as well as in demographic growth are directly linked to contraceptive usage. The development and availability of safer, improved contraceptives which are convenient to use could be expected to be used by a larger group of individuals and thus make an impact on reproductive health as well as on population growth rates. Such arguments have been used to support contraceptive research. This article deals with some of the developments that have occurred as a consequence of such efforts.

Recent innovations in synthetic drug delivery systems

Recent innovations in synthetic drug delivery systems