Nanomaterials innovation as an enabler for effective cancer interventions.

Nanomedicines have been developing very rapidly and have started to play a significant role in several cancer therapeutic modalities. Early on, the nanomedicine field focused on optimizing pharmacokinetics, toxicity, and/or biodistribution of an agent through nanoparticle formulation. In other cases, where materials science is employed more decisively, nanomedicine can include the creation of new agents that take advantage of nanoscale materials properties to enhance treatment efficacy through unique mode of action, molecular targeting, or controlled drug release. Both current and future nanomedicines will seek to contribute to the therapeutic and diagnostic landscape through creative leveraging of mechanical, electrical, optical, magnetic, and biological nanomaterial properties. In this work, we discuss how by modulating these material properties, one can design more diverse and more effective cancer interventions. We focus on six areas in cancer management, including in vitro diagnostics, clinical imaging, theranostics, combination therapy, immunotherapy, and gene therapy.

National Cancer Institute Alliance for nanotechnology in cancer-Catalyzing research and translation toward novel cancer diagnostics and therapeutics.

Nanotechnology has been a burgeoning research field, which is finding compelling applications in several practical areas of everyday life. It has provided novel, paradigm shifting solutions to medical problems and particularly to cancer. In order to accelerate integration of nanotechnology into cancer research and oncology, the National Cancer Institute (NCI) of the National Institutes of Health (NIH) established the NCI Alliance for Nanotechnology in Cancer program in 2005. This effort brought together scientists representing physical sciences, chemistry, and engineering working at the nanoscale with biologists and clinicians working on cancer to form a uniquely multidisciplinary cancer nanotechnology research community. The last 14 years of the program have produced a remarkable body of scientific discovery and demonstrated its utility to the development of practical cancer interventions. This paper takes stock of how the Alliance program influenced melding of disparate research disciplines into the field of nanomedicine and cancer nanotechnology, has been highly productive in the scientific arena, and produced a mechanism of seamless transfer of novel technologies developed in academia to the clinical and commercial space. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

NCI Alliance for Nanotechnology in Cancer - from academic research to clinical interventions.

The National Cancer Institute (NCI) of National Institutes of Health has funded and operated the NCI Alliance for Nanotechnology in Cancer - a large multi-disciplinary program which leverages research at the intersection of molecular biology, oncology, physics, chemistry, and engineering to develop innovative cancer interventions. The program has demonstrated that convergence of several scientific disciplines catalyzes innovation and progress in cancer nanotechnology and advances its clinical translation. This paper takes a look at last thirteen years of the Alliance program operations and delineates its outcomes, successes, and outlook for the future.

Chemotherapeutic Drug Delivery and Quantitative Analysis of Proliferation, Apoptosis, and Migration in a Tissue-Engineered Three-Dimensional Microvessel Model of the Tumor Microenvironment.

Numerous approaches have been employed to improve the efficacy of drug and gene delivery systems, but their strategic development is hindered by a lack of mechanistic understanding and assessment of drug transport and action. Optimizing the efficiency of a drug delivery system requires a detailed understanding of the pharmacokinetics, transendothelial transport, distribution at the tumor site, and uptake in target cells. Elucidating transport kinetics and rate-limiting steps in animal models can be extremely challenging, while in vitro platforms often fail to recapitulate the complexities of drug transport in vivo. To recapitulate the critical aspects of delivery of anticancer agents, we have developed a 3D tissue-engineered microvessel model of the tumor microenvironment. Our model consists of single MDA-MB-231 breast cancer cells embedded within a collagen matrix that surrounds a perfusable cylindrical microvessel lined with human endothelial cells. Here we compare transport and action of free doxorubicin and Doxil, a liposomal formulation of doxorubicin. We show that the mode of drug delivery influences uptake in the vessel endothelium and tumor cells. Through quantification of endothelial and tumor cell proliferation, apoptosis, and motility, we profile the kinetics of drug action with mechanisms of drug transport across the vessel lumen and into the surrounding matrix. Our model can be customized to mimic specific tumor microenvironments and disease states within a physiologically relevant microfluidic platform and provides a basis for characterizing and optimizing drug delivery systems.

Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action.

Doxil, a liposomal formulation of the chemotherapeutic drug doxorubicin, is FDA-approved for multiple indications. Doxil liposomes are designed to retain doxorubicin in circulation, minimize clearance by the mononuclear phagocyte system, and limit uptake in healthy tissue. Although pharmacokinetic data and survival statistics from clinical trials provide insight into distribution and efficacy, many details of the mechanism of action remain unresolved, despite the importance in translating liposome-based drug delivery systems to other molecules and cargo. Therefore, the objective of this study is to quantitatively assess the kinetics of doxorubicin leakage from Doxil liposomes. In contrast to previous studies, we consider three processes: dissolution of solid doxorubicin, protonation/deprotonation of soluble doxorubicin, and passive transport of neutral doxorubicin across the lipid bilayer of the liposomes. Experiments were performed for Doxil, Doxil-like liposomes, and Doxil-like liposomes with reduced cholesterol and pegylation. To mimic physiological conditions, we also performed experiments in serum and under slightly acidic conditions at pH5. We show that crystalline doxorubicin dissolution can be described by a first order rate constant of 1.0×10-9cms-1 at 37°C. Doxorubicin leakage can be described by first order rate constant for transport across the lipid bilayer with values in the range from 1 to 3×10-12cms-1 at 37°C. Based on these results we discuss implications for the mechanism of action, taking Doxil pharmacokinetics into account.

Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency.

Systemic drug delivery to a solid tumor involves a sequence of steps that determine efficacy and survival. Extravasation from circulation at the tumor site is a critical step in this sequence since it regulates how much of the drug accumulates in the tumor. Despite its importance in determining outcomes, extravasation from circulation remains a "black box." The objective of this study is to develop predictive tools for optimization of drug delivery systems. By comparing pharmacokinetics of liposomal doxorubicin in tumor-free and tumor bearing mice we quantitatively assess the rate constants for distribution, elimination, and tumor accumulation. We then relate these rate constants to the tumor-type and drug delivery system. We compare tumor accumulation in three tumor types and show a 10-fold difference between a colorectal adenocarcinoma and a pancreatic adenocarcinoma. Finally, we show how quantitative predictions of changes in tumor accumulation can be used to optimize drug delivery systems.

Quantitative Evaluation of the Enhanced Permeability and Retention (EPR) Effect.

Quantitative evaluation of nanoparticle delivery to a tumor site can be invaluable for cross-platform comparison, a consideration not currently taken into account by many in the field of cancer nanomedicine (Dawidczyk et al., Front Chem 2:69, 2014). Standardization of measured parameters and experimental design will facilitate nanoparticle design and understanding in the field. Here, we present a broadly applicable in vivo protocol for preclinical trials of nanomedicines, including pharmacokinetic modeling and recommendations for parameters to be reported for nanoparticle evaluation. The proposed protocol is simple and not prohibitively mouse-heavy, using procedures that are not overly complicated or difficult to learn, yet is a powerful way to analyze the effectiveness of new cancer nanomedicines against standard or more developed ones.

Development and Application of a Novel Model System to Study "Active" and "Passive" Tumor Targeting.

Macromolecular reagents can be targeted to tumors through active and passive mechanisms. "Active" targeting involves moieties, such as receptor ligands, to direct tumor cell binding, whereas "passive" targeting relies on long reagent circulating half-life, abnormal tumor vasculature, and poor lymphatic drainage for tumor entrapment. Here, we sought to study the impact of reagent circulating half-life on "active" and "passive" tumor uptake. The humanized prostate-specific membrane antigen (PSMA)-targeting antibody HuJ591 was used as the "active" targeting agent. HuJ591 was labeled with a Near Infrared (NIR) dye and its circulating half-life was modified by conjugation to high-molecular-weight Polyethylene Glycol (PEG). PEGylation did not negatively impact PSMA-binding specificity. "Active" and "passive" tumor targeting of intravenously injected antibody conjugates were then quantified by NIR fluorescent imaging of immunocompromised mice bearing bilateral isogenic PSMA-positive and PSMA-negative human tumor xenografts. Two isogenic tumor pairs were applied, PC3 ± PSMA (PC3-PIP/PC3-Flu) or LMD-MDA-MB-231 ± PSMA (LMD-PSMA/LMD). This study provided a unique model system to simultaneously observe "active" and "passive" tumor targeting within a single animal. "Passive" targeting was observed in all PSMA-negative tumors, and was not enhanced by increased HuJ591 size or extended circulating half-life. Interestingly, "active" targeting was only successful in some situations. Both PSMA-positive tumor models could be actively targeted with J591-IR800 and J591-PEG10K. However, the larger J591-PEG30K enhanced "active" targeting in the PC-3 tumor models, but inhibited "active" targeting the LMD-MDA-MB-231 tumor model. Successful "active" targeting was associated with higher PSMA expression. These results support the potential for "active" targeting to enhance overall macromolecular reagent uptake within tumors. Mol Cancer Ther; 15(10); 2541-50. ©2016 AACR.

Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies.

Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments.

The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics, tumor accumulation, and biodistribution. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field.

State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines.

The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs.