Erik Robinson

Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment

Nanodiamond-based drug delivery significantly enhanced treatment efficacy and safety in multiple chemoresistant cancer models. Nanodiamonds Are a Girl’s Best Friend When it comes to diamonds on the finger or ear lobes, bigger is better. However, for drug delivery, a small diamond may be the key to overcoming drug resistance in cancer. Nanodiamonds—tiny carbon particles—are biocompatible, can be scalably synthesized, and can bind therapeutic agents, features that make them a promising platform for drug delivery. Now, Chow et al. have found that binding nanodiamonds to the anticancer drug doxorubicin (Dox) improved therapeutic response and overcame chemoresistance in mouse models of mammary and liver cancer. Believed to act by interfering with DNA synthesis, Dox is commonly used to treat a wide variety of cancers; however, many cancers become resistant to Dox during treatment due in part to efflux of the drug from the tumor cells. In an attempt to overcome tumor chemoresistance, Chow et al. conjugated Dox to nanodiamonds as a possible means of preventing the drug from being pumped out of cells. Indeed, the nanodiamond-Dox complexes were retained better by cancer cells, decreased tumor growth, and displayed less toxicity in mammary and liver cancer mouse models when compared with unconjugated Dox. The gradual release of Dox from the nanodiamonds allowed for enhanced tumor retention and efficacy, but the small size allowed for clearance before toxicity occurred in slower-dividing healthy tissues. Thus, nanodiamonds may provide a drug delivery platform that has it all—improved safety profiles and enhanced efficacy. Like their much larger predecessor, nanodiamonds are truly diamonds of Hope. Enhancing chemotherapeutic efficiency through improved drug delivery would facilitate treatment of chemoresistant cancers, such as recurrent mammary tumors and liver cancer. One way to improve drug delivery is through the use of nanodiamond (ND) therapies, which are both scalable and biocompatible. Here, we examined the efficacy of an ND-conjugated chemotherapeutic in mouse models of liver and mammary cancer. A complex (NDX) of ND and doxorubicin (Dox) overcame drug efflux and significantly increased apoptosis and tumor growth inhibition beyond conventional Dox treatment in both murine liver tumor and mammary carcinoma models. Unmodified Dox treatment represents the clinical standard for most cancer treatment regimens, and NDX had significantly decreased toxicity in vivo compared to standard Dox treatment. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for overcoming chemoresistance and enhancing chemotherapy efficacy and safety.

Nanodiamond-insulin complexes as pH-dependent protein delivery vehicles

Enhanced specificity in drug delivery aims to improve upon systemic elution methods by locally concentrating therapeutic agents and reducing negative side effects. Due to their robust physical properties, biocompatibility and drug loading capabilities, nanodiamonds serve as drug delivery platforms that can be applied towards the elution of a broad range of therapeutically-active compounds. In this work, bovine insulin was non-covalently bound to detonated nanodiamonds via physical adsorption in an aqueous solution and demonstrated pH-dependent desorption in alkaline environments of sodium hydroxide. Insulin adsorption to NDs was confirmed by FT-IR spectroscopy and zeta potential measurements, while both adsorption and desorption were visualized with TEM imaging, quantified using protein detection assays and protein function demonstrated by MTT and RT-PCR. NDs combined with insulin at a 4:1 ratio showed 79.8+/-4.3% adsorption and 31.3+/-1.6% desorption in pH-neutral and alkaline solutions, respectively. Additionally, a 5-day desorption assay in NaOH (pH 10.5) and neutral solution resulted in 45.8+/-3.8% and 2.2+/-1.2% desorption, respectively. MTT viability assays and quantitative RT-PCR (expression of Ins1 and Csf3/G-csf genes) reveal bound insulin remains inactive until alkaline-mediated desorption. For applications in sustained drug delivery and therapy we have developed a therapeutic protein-ND complex with demonstrated tunable release and preserved activity.

Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment

UNLABELLED This study examined a novel drug delivery system for treatment of malignant brain gliomas: DOX complexed with nanodiamonds (ND-Dox), and administered via convection-enhanced delivery (CED). Drug retention and toxicity were examined in glioma cell lines, and distribution, retention and toxicity were examined in normal rat parenchyma. Efficacy was assessed in a bioluminescence rodent tumor model. NDs markedly enhanced DOX uptake and retention in glioma cells. ND-Dox delivered via CED extended DOX retention and localized DOX toxicity in normal rodent parenchyma, and was significantly more efficient at killing tumor cells than uncomplexed DOX. Outcomes from this work suggest that CED of ND-Dox is a promising approach for brain tumor treatment. FROM THE CLINICAL EDITOR In this paper, nanodiamonds were utilized to enhance delivery of DOX in a preclinical glioma model using a convection-enhanced delivery method, demonstrating remarkably enhanced efficacy.

Synthesis of nanodiamond-daunorubicin conjugates to overcome multidrug chemoresistance in leukemia

UNLABELLED Nanodiamonds (NDs) are promising candidates in nanomedicine, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. We have synthesized ND vectors capable of chemotherapeutic loading and delivery with applications towards chemoresistant leukemia. The loading of Daunorubicin (DNR) onto NDs was optimized by adjusting reaction parameters such as acidity and concentration. The resulting conjugate, a novel therapeutic payload for NDs, was characterized extensively for size, surface charge, and loading efficiency. A K562 human myelogenous leukemia cell line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains. FROM THE CLINICAL EDITOR The authors of this study demonstrate superior treatment properties of resistant leukemia cell lines by utilizing nanodiamond vectors loaded with daunorubicin, paving the way to clinical studies in the hopefully not too distant future.

Ultrananocrystalline Diamond Thin Films Functionalized with Therapeutically Active Collagen Networks

The fabrication of biologically amenable interfaces in medicine bridges translational technologies with their surrounding biological environment. Functionalized nanomaterials catalyze this coalescence through the creation of biomimetic and active substrates upon which a spectrum of therapeutic elements can be delivered to adherent cells to address biomolecular processes in cancer, inflammation, etc. Here, we demonstrate the robust functionalization of ultrananocrystalline diamond (UNCD) with type I collagen and dexamethasone (Dex), an anti-inflammatory drug, to fabricate a hybrid therapeutically active substrate for localized drug delivery. UNCD oxidation coupled with a pH-mediated collagen adsorption process generated a comprehensive interface between the two materials, and subsequent Dex integration, activity, and elution were confirmed through inflammatory gene expression assays. These studies confer a translational relevance to the biofunctionalized UNCD in its role as an active therapeutic network for potent regulation of cellular activity toward applications in nanomedicine.

Localized therapeutic release via an amine-functionalized poly-p-xylene microfilm device.

Developing biocompatible polymeric platforms for drug delivery with enhanced localized activity represents a key facet of advanced interventional therapy. In this work, the drug-eluting potential of an amine-functionalized poly- p-xylene commonly known as Parylene A (4-amino(2,2)paracyclophane) was conducted with the microfilm device consisting of a primary base layer, drug film, and a secondary eluting layer presenting exposed amine groups which enhance the range of modifications that can be incorporated into the film. The murine macrophage cell line RAW 264.7 served as a cellular response to dexamethasone, a synthetic anti-inflammatory glucocorticoid and doxorubicin, an anticancer therapeutic. Decreased expression of NFkappa-B-mediated cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNFalpha), resultant DNA fragmentation, and spectroscopic analysis revealed the efficient and localized drug-eluting properties of the Parylene A polymeric bilayer.

Engineering Multifunctional Biologically-Amenable Nanomaterials for Interfacial Therapeutic Delivery and Substrate-Based Cellular Interrogation

The advent of materials that can enhance the interfaces between biological tissue and engineered devices will enable unprecedented medical capabilities in the context of prolonged implantation, and novel information gleaned from cellular interrogation, etc. This work addresses a spectrum of novel technologies that can serve a broad range of therapeutically relevant scenarios ranging from inflammation attenuation to stand-alone chemotherapeutic delivery systems. They include copolymer-based multifunctional platforms that can be applied towards dynamic cell adhesion/patterning, drug delivery, and localized manipulation of key cyto-regulatory networks for clinical applications. In addition, soluble nanodiamond platforms in free-floating or thin film platforms will be addressed as next generation therapeutic vehicles. In addition to cytokine expression knockdown studies as well as in vivo validation of their efficacy, this suite of modalities successfully addresses a key element of optimized interfacing based upon innate biocompatibility which has been verified at the genetic level, confirming their potential clinical significance.

Chapter 15 – Engineering Nanoparticulate Diamond for Applications in Nanomedicine and Biology

There is increasing evidence that nanodiamonds (NDs) can be effectively utilized as a platform for a variety of diagnostic and therapeutic applications. This nanoparticle possesses a number of key advantages including remarkable biocompatibility across different cell types, ease and breadth of surface modification, and unique optical and electronic properties. Nanocrystalline diamond films also represent an amenable surface to a variety of biomedical applications. To fully utilize NDs for medicine, purification, deagglomeration, and functionalization procedures are required to disintegrate tight ND aggregates into primary particles ( in vitro , from chemotherapeutics to nucleic acids. They also exhibit extraordinary fluorescence capabilities after minor chemical modifications, allowing for use in biological tracking experiments. Their impressive applicability toward drug delivery extends to in vivo experiments as well, where NDs were shown to overcome drug resistance in a comprehensive murine model-based study. Compared to using drug alone, the ND–drug conjugates showed more robust treatment against mammary and liver tumors. Subsequently, this result confirms the powerful therapeutic sequestering and targeting effect of NDs, and its potential for improving the ability to treat a broad spectrum of diseases such as cancer.