Dean Ho

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.

Polymer-functionalized nanodiamond platforms as vehicles for gene delivery.

Gene therapy holds great promise for treating diseases ranging from inherited disorders to acquired conditions and cancers. Nonetheless, because a method of gene delivery that is both effective and safe has remained elusive, these successes were limited. Functional nanodiamonds (NDs) are rapidly emerging as promising carriers for next-generation therapeutics with demonstrated potential. Here we introduce NDs as vectors for in vitro gene delivery via surface-immobilization with 800 Da polyethyleneimine (PEI800) and covalent conjugation with amine groups. We designed PEI800-modified NDs exhibiting the high transfection efficiency of high molecular weight PEI (PEI25K), but without the high cytotoxicity inherent to PEI25K. Additionally, we demonstrated that the enhanced delivery properties were exclusively mediated by the hybrid ND-PEI800 material and not exhibited by any of the materials alone. This platform approach represents an efficient avenue toward gene delivery via DNA-functionalized NDs, and serves as a rapid, scalable, and broadly applicable gene therapy strategy.

Cancer Nanomedicine: From Drug Delivery to Imaging

Nanomedicine has made progress in translating to cancer treatment and imaging, but challenges still remain. Nanoformulated drugs, genes, and imaging agents have the opportunity to improve cancer treatment and diagnosis. This Review describes the many approaches to nanomedicine, how they are being tested for cancer therapy and imaging, and what obstacles remain in translation. Nanotechnology-based chemotherapeutics and imaging agents represent a new era of “cancer nanomedicine” working to deliver versatile payloads with favorable pharmacokinetics and capitalize on molecular and cellular targeting for enhanced specificity, efficacy, and safety. Despite the versatility of many nanomedicine-based platforms, translating new drug or imaging agents to the clinic is costly and often hampered by regulatory hurdles. Therefore, translating cancer nanomedicine may largely be application-defined, where materials are adapted only toward specific indications where their properties confer unique advantages. This strategy may also realize therapies that can optimize clinical impact through combinatorial nanomedicine. In this review, we discuss how particular materials lend themselves to specific applications, the progress to date in clinical translation of nanomedicine, and promising approaches that may catalyze clinical acceptance of nano.

Nanodiamond-mediated delivery of water-insoluble therapeutics.

A broad array of water-insoluble compounds has displayed therapeutically relevant properties toward a spectrum of medical and physiological disorders, including cancer and inflammation. However, the continued search for scalable, facile, and biocompatible routes toward mediating the dispersal of these compounds in water has limited their widespread application in medicine. Here we demonstrate a platform approach of water-dispersible, nanodiamond cluster-mediated interactions with several therapeutics to enhance their suspension in water with preserved functionality, thereby enabling novel treatment paradigms that were previously unrealized. These therapeutics include Purvalanol A, a highly promising compound for hepatocarcinoma (liver cancer) treatment, 4-hydroxytamoxifen (4-OHT), an emerging drug for the treatment of breast cancer, as well as dexamethasone, a clinically relevant anti-inflammatory that has addressed an entire spectrum of diseases that span complications from blood and brain cancers to rheumatic and renal disorders. Given the scalability of nanodiamond processing and functionalization, this novel approach serves as a facile, broadly impacting and significant route to translate water-insoluble compounds toward treatment-relevant scenarios.

Protein-Mediated Assembly of Nanodiamond Hydrogels into a Biocompatible and Biofunctional Multilayer Nanofilm

Aqueous dispersible detonation nanodiamonds (NDs) with a diameter of 2-8 nm were assembled into a closely packed ND multilayer nanofilm with positively charged poly-L-lysine via the layer-by-layer deposition technique. The innate biocompatibility of the NDs in both free-floating and thin-film forms was confirmed via cellular gene expression examination by real-time polymerase chain reaction as well as MTT and DNA fragmentation assays. The highly biologically amenable ND nanofilm was successfully integrated with therapeutic molecules, and the functionality of the composite drug-ND material was assessed via interrogation of the suppression of inflammatory cytokine release. Knockdown of lipopolysaccharide-mediated inflammation was observed through the potent attenuation of tumor necrosis factor-alpha, interleukin-6, and inducible nitric oxide synthase levels following ND nanofilm interfacing with RAW 264.7 murine macrophages. Furthermore, basal cytokine secretion levels were assessed to examine innate material biocompability, revealing unchanged cellular inflammatory responses which strongly supported the relevance of the NDs as effective treatment platforms for nanoscale medicine. In addition to the easy preparation, robustness, and fine controllability of the film structures, these hybrid materials possess enormous potential for biomedical applications such as localized drug delivery and anti-inflammatory implant coatings and devices, as demonstrated in vitro in this work.

Nanodiamond-Embedded Microfilm Devices for Localized Chemotherapeutic Elution

Nanodiamonds (NDs) of 2-8 nm diameters physically bound with the chemotherapeutic agent doxorubicin hydrochloride (DOX) were embedded within a parylene C polymer microfilm through a facile and scalable process. The microfilm architecture consists of DOX-ND conjugates sandwiched between a base and thin variable layer of parylene C which allows for modulation of release. Successive layers of parylene and the DOX-ND conjugates were characterized through atomic force microscopy (AFM) images and drug release assays. Elution rates were tested separately over a period of 8 days and up to one month in order to illustrate the release characteristics of the microfilms. The microfilms displayed the stable and continuous slow-release of drug for at least one month due to the powerful sequestration abilities of the DOX-ND complex and the release-modulating nature of the thin parylene layer. Since the fabrication process is devoid of any destructive steps, the DOX-ND conjugates are unaffected and unaltered. A DNA fragmentation assay was performed to illustrate this retained activity of DOX under biological conditions. Specifically, in this work we have conferred the ability to tangibly manipulate the NDs in a polymer-packaged microfilm format for directed placement over diseased areas. By harnessing the innate ND benefits in a biostable patch platform, extended targeted and controlled release, possibly relevant toward conditions such as cancer, viral infection, and inflammation, where complementary alternatives to systemic drug release enabled by the microfilm devices, can allow for enhanced treatment efficacy.

Multimodal nanodiamond drug delivery carriers for selective targeting, imaging, and enhanced chemotherapeutic efficacy.

The advancement of next-generation nanocarriers as drug delivery platforms will require the incorporation of these useful properties, through which adverse side effects of chemotherapy drugs can be avoided and overall treatment and diagnosis improved. As such, a variety of nanoparticle-based delivery systems have already been widely investigated and provided interesting avenues of research for improving cancer treatments through therapy and targeted delivery. [ 2–7 ]

Accelerating the Translation of Nanomaterials in Biomedicine

Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples.

Diamond‐Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression

Self-assembled nanodiamond-lipid hybrid particles (NDLPs) harness the potent interaction between the nanodiamond (ND)-surface and small molecules, while providing a mechanism for cell-targeted imaging and therapy of triple negative breast cancers. Epidermal growth factor receptor-targeted NDLPs are highly biocompatible particles that provide cell-specific imaging, promote tumor retention of ND-complexes, prevent epirubicin toxicities and mediate regression of triple negative breast cancers.

Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells.

Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond–drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.