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The field of nanomedicine has already seen substantial progress in the clinic, with multiple formulations being evaluated through clinical studies. From poly(lactic-co-glycolic acid) and cyclodextrin-based drug-delivery platforms to metallic nanoparticles for photothermal treatment and imaging, nanotechnology has enabled versatile strategies to treat and to diagnose a wide range of disorders. However, as the field as a whole pushes forward, barriers that have always challenged conventional drug development have already started to impact nanomedicine translation. These include exorbitant costs, substantial time to development, and the uncertainty of achieving major improvements in efficacy or safety. Of note, there has been, until recent advances, a virtual inability to identify optimal drug doses either as monotherapies or components of combination therapy. In this Nano Focus, we assess how the impact of nanotechnology in the clinic can be optimized through systematically designed combinatorial nanotherapy. In addition, we provide a clinical perspective on how a recently unveiled technology platform can substantially alter the landscape of combinatorial nanomedicine, drug development, as well as conventional drug development.

Detonation nanodiamonds (DNDs) have been widely explored for biomedical applications ranging from cancer therapy to magnetic resonance imaging due to several promising properties. These include faceted surfaces that mediate potent drug binding and water coordination that have resulted in marked enhancements to the efficacy and safety of drug delivery and imaging. In addition, scalable processing of DNDs yields uniform particles. Furthermore, a broad spectrum of biocompatibility studies has shown that DNDs appear to be well-tolerated. Prior to the clinical translation of DNDs for indications that are addressed via intravenous administration, comprehensive assessment of DND safety in both small and large animal preclinical models is needed. This article reports the results of a DND biocompatibility study in both non-human primates and rats. The rat study was performed as a multiple dose subacute investigation in two cohorts that lasted for 2 weeks and included histological, serum, and urine analysis. The non-human primate study was performed as a dual gender, multiple dose, and long-term investigation in both standard/clinically relevant and elevated dosing cohorts that lasted for 6 months and included comprehensive serum, urine, histological, and body weight analysis. The results from these studies indicate that NDs are well-tolerated at clinically relevant doses. Examination of dose-dependent changes in biomarker levels provides important guidance for the downstream in-human validation of DNDs for clinical drug delivery and imaging.

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.

Chemoresistance is a prevalent issue that accounts for the vast majority of treatment failure outcomes in metastatic cancer. Among the mechanisms of resistance that markedly decrease treatment efficacy, the efflux of drug compounds by ATP-binding cassette (ABC) transporter proteins can impair adequate drug retention by cancer cells required for therapeutic cytotoxic activity. Of note, ABC transporters are capable of effluxing several classes of drugs that are clinical standards, including the anthracyclines such as doxorubicin, as well as anthracenediones such as mitoxantrone. To address this challenge, a spectrum of nanomaterials has been evaluated for improved drug retention and enhanced efficacy. Nanodiamonds (NDs) are emerging as a promising nanomaterial platform because they integrate several important properties into a single agent. These include a uniquely faceted truncated octahedral architecture that enables potent drug binding and dispersibility in water, scalably processed ND particles with uniform diameters of approximately 5 nm, and a demonstrated ability to improve drug tolerance while delaying tumor growth in multiple preclinical models, among others. This work describes a ND-mitoxantrone complex that can be rapidly synthesized and mediates marked improvements in drug efficacy. Comprehensive complex characterization reveals a complex with favorable drug delivery properties that is capable of improving drug retention and efficacy in an MDA-MB-231-luc-D3H2LN (MDA-MB-231) triple negative breast cancer cell line that was lentivirally transduced for resistance against mitoxantrone. Findings from this study support the further evaluation of ND-MTX in preclinical dose escalation and safety studies toward potentially clinical validation.

Nanomaterials such as block copolymeric membranes provide a platform for both cellular interrogation and biological mimicry. Their biomimetic properties are based upon the innate possession of hydrophilic and hydrophobic units that enable their integration with a broad range of therapeutic materials. As such, they can be engineered for specific applications in nanomedicine, including controlled/localized drug delivery. Here we describe a method for the functionalization of the polymethyloxazoline-polydimethylsiloxane-polymethyloxazoline (PMOXA-PDMS-PMOXA) block copolymer with anti-inflammatory molecules to develop copolymer-therapeutic hybrids, effectively conferring biological functionality to a versatile synthetic nanomembrane matrix and creating a platform for an anti-inflammatory drug delivery system. Utilizing self-assembly and Langmuir-Blodgett deposition methods, we mixed copolymers with dexamethasone (Dex), an anti-inflammatory glucocorticoid receptor agonist. The successful mixing of the copolymer with the drug was confirmed by surface pressure isotherms and fluorescence microscopy. Furthermore, at 4 nm thick per layer, orders of magnitude thinner than conventional drug delivery coatings, these dexamethasone-copolymer mixtures (PolyDex) suppressed in vitro expression of the inflammatory cytokines/signaling elements interleukin 6 (IL-6), interleukin 12 (IL-12), tumor necrosis factor alpha (TNFalpha), inducible nitric oxide synthase (iNOS), and interferon gamma inducible protein (IP-10). Finally, PolyDex maintained its anti-inflammatory properties in vivo confirmed through punch biopsies with tissue imagery via hematoxylin/eosin and macrophage specific staining using CD11b. Thus, we demonstrated that PolyDex may be utilized as a localized, highly efficient drug-copolymer composite for active therapeutic delivery to confer anti-inflammatory protection or as a platform material for broad drug elution capabilities.