Xue-Qing Zhang

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.

Gd(III)-Nanodiamond Conjugates for MRI Contrast Enhancement

A Gd(III)-nanodiamond conjugate [Gd(III)-ND] was prepared and characterized, enabling detection of nanodiamonds by MR imaging. The Gd(III)-ND particles significantly reduced the T(1) of water protons with a per-Gd(III) relaxivity of 58.82 +/- 1.18 mM(-1) s(-1) at 1.5 T (60 MHz). This represents a 10-fold increase compared to the monomer Gd(III) complex (r(1) = 5.42 +/- 0.20 mM(-1) s(-1)) and is among the highest per-Gd(III) relaxivities reported.

Cancer nanomedicine: from targeted delivery to combination therapy.

The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy.

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.

Interactions of nanomaterials and biological systems: implications to personalized nanomedicine

The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials.

Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug

Significance The development of acquired chemoresistance is often a clinical problem limiting the successful treatment of cancers. RNAi is showing promising results in human clinical trials. The combination of chemotherapy with RNAi approaches to suppress the expression of proteins involved in the emergence of drug resistance represents a promising synergistic strategy to circumvent or reverse acquired chemoresistance. Such combination therapy approaches require specific delivery vehicles to encapsulate and deliver chemotherapy and siRNA therapeutics simultaneously in a controlled manner. Herein, we describe a nanoparticle technology to codeliver a DNA-damaging chemotherapeutic and siRNAs that impair the cell’s ability to repair the DNA damage. This combination therapeutic approach can sensitize cancer cells to chemotherapeutics and shows superior tumor inhibition compared with monochemotherapy. Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.

Multimodal Gadolinium-Enriched DNA–Gold Nanoparticle Conjugates for Cellular Imaging†

During the past two decades, magnetic resonance imaging (MRI) has become a powerful technique in clinical diagnosis and biological molecular imaging.[1–4] A signficant advantage of MRI is the ability to acquire tomographic information of whole animals with high spatial resolution and soft tissue contrast. In addition, images are acquired without the use of ionizing radiation (e.g., X-ray and CT) or radiotracers (e.g., PET and SPECT) permitting long term longitudinal studies. Since spatial resolution increases with magnetic field strength, the ability to track small cell populations has been realized.

Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles

Significance Obesity has been recognized by the American Medical Association to be a disease affecting significant portions of the population and is related to an expansion and proliferation of white adipose tissue (WAT) in the body. The primary function of WAT is to store energy, whereas brown adipose tissue (BAT) generates heat through energy expenditure. Transforming WAT into BAT is of tremendous interest for obesity treatment. Herein, we describe a targeted nanoparticle approach encapsulating either a PPARgamma activator or a prostaglandin E2 analog, each of which induces adipose tissue transformation and angiogenesis, facilitating the transformation of WAT into BAT. Targeted nanoparticles show antiobesity effects compared with free drug and the nontargeted nanoparticle controls in a mouse model. The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.

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 ]