Microfluidic technologies for accelerating the clinical translation of nanoparticles

Using nanoparticles for therapy and imaging holds tremendous promise for the treatment of major diseases such as cancer. However, their translation into the clinic has been slow because it remains difficult to produce nanoparticles that are consistent 'batch-to-batch', and in sufficient quantities for clinical research. Moreover, platforms for rapid screening of nanoparticles are still lacking. Recent microfluidic technologies can tackle some of these issues, and offer a way to accelerate the clinical translation of nanoparticles. In this Progress Article, we highlight the advances in microfluidic systems that can synthesize libraries of nanoparticles in a well-controlled, reproducible and high-throughput manner. We also discuss the use of microfluidics for rapidly evaluating nanoparticles in vitro under microenvironments that mimic the in vivo conditions. Furthermore, we highlight some systems that can manipulate small organisms, which could be used for evaluating the in vivo toxicity of nanoparticles or for drug screening. We conclude with a critical assessment of the near- and long-term impact of microfluidics in the field of nanomedicine.Prostate Cancer Foundation (Award in Nanotherapeutics)MIT-Harvard Center for Cancer Nanotechnology Excellence (U54-CA151884)National Heart, Lung, and Blood Institute (Programs of Excellence in Nanotechnology (HHSN268201000045C))National Science Foundation (U.S.) (Graduate Research Fellowship

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Introduction: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles are one technology being developed to enable clinically feasible oral delivery. Areas Covered: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal barriers using polymeric nanoparticles will be considered, including mucoadhesive biomaterials and targeting of nanoparticles to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations. Expert Opinion: There have been many approaches used to overcome the transport barriers presented by the gastrointestinal tract, but most have been limited by low bioavailability. Recent strategies targeting nanoparticles to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and nanoparticles across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric nanoparticle technologies and enable the translation of these technologies to clinical practice

Poly(ethylene glycol) with Observable Shedding

A novel FRET-bearing poly(ethylene glycol) (PEG) conjugate fluoresces at 520 nm when it is cleaved off from nanoparticles (NPs). When the NPs were targeted to cancer cell lines, the reducing redox of the endosomal compartment caused disulfide bond cleavage and shedding of the PEG layer. The fluorescence emission can be suppressed by N-ethylmaleimide to inhibit disulfide cleavage and restored by dithiothreitol, a disulfide cleavage reagent, indicating a direct correlation between fluorescence emission and PEG shedding

DNA Self-Assembly of Targeted Near-Infrared-Responsive Gold Nanoparticles for Cancer Thermo-Chemotherapy

Targeted Cancer Therapy: Inspired by the ability of DNA hybridization, a targeted near-infrared (NIR) light-responsive delivery system has been developed through simple DNA self-assembly (PEG=polyethylene glycol). This DNA-based platform shows the ability of releasing therapeutics upon near-infrared irradiation, and remarkable targeted thermo- and chemotherapeutic efficacy in vitro and in vivo

Microfluidic Platform for Combinatorial Synthesis and Optimization of Targeted Nanoparticles for Cancer Therapy

Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to nontargeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to nontargeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs.Prostate Cancer Foundation (Award in Nanotherapeutics)National Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence at MIT-Harvard U54-CA151884National Heart, Lung, and Blood Institute (Programs of Excellence in Nanotechnology HHSN268201000045C)National Science Foundation (U.S.). Graduate Research FellowshipAmerican Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipNational Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence. Graduate Research Fellowship

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

Surface Charge-Switching Polymeric Nanoparticles for Bacterial Cell Wall-Targeted Delivery of Antibiotics

Bacteria have shown a remarkable ability to overcome drug therapy if there is a failure to achieve sustained bactericidal concentration or if there is a reduction in activity in situ. The latter can be caused by localized acidity, a phenomenon that can occur as a result of the combined actions of bacterial metabolism and the host immune response. Nanoparticles (NP) have shown promise in treating bacterial infections, but a significant challenge has been to develop antibacterial NPs that may be suitable for systemic administration. Herein we develop drug-encapsulated, pH-responsive, surface charge-switching poly(d,l-lactic-co-glycolic acid)-b-poly(l-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for treating bacterial infections. These NP drug carriers are designed to shield nontarget interactions at pH 7.4 but bind avidly to bacteria in acidity, delivering drugs and mitigating in part the loss of drug activity with declining pH. The mechanism involves pH-sensitive NP surface charge switching, which is achieved by selective protonation of the imidazole groups of PLH at low pH. NP binding studies demonstrate pH-sensitive NP binding to bacteria with a 3.5 ± 0.2- to 5.8 ± 0.1-fold increase in binding to bacteria at pH 6.0 compared to 7.4. Further, PLGA-PLH-PEG-encapsulated vancomycin demonstrates reduced loss of efficacy at low pH, with an increase in minimum inhibitory concentration of 1.3-fold as compared to 2.0-fold and 2.3-fold for free and PLGA-PEG-encapsulated vancomycin, respectively. The PLGA-PLH-PEG NPs described herein are a first step toward developing systemically administered drug carriers that can target and potentially treat Gram-positive, Gram-negative, or polymicrobial infections associated with acidity.National Institutes of Health (U.S.) (Grant CA151884)National Institutes of Health (U.S.) (Grant EB003647)Prostate Cancer Foundation (Award in Nanotherapeutics)United States. Dept. of Defense (Prostate Cancer Research Program PC 051156)MIT-Portugal ProgramNational Science Foundation (U.S.). Graduate Research FellowshipNational Institutes of Health (U.S.) (Office of the Director Grant DP2OD008435

Immunocompatibility properties of lipid–polymer hybrid nanoparticles with heterogeneous surface functional groups

Here we report the immunological characterization of lipid-polymer hybrid nanoparticles (NPs) and propose a method to control the levels of complement activation induced by these NPs. This method consists of the highly specific modification of the NP surface with methoxyl, carboxyl, and amine groups. Hybrid NPs with methoxyl surface groups induced the lowest complement activation, whereas the NPs with amine surface groups induced the highest activation. All possible combinations among carboxyl, amine, and methoxyl groups also activated the complement system to a certain extent. All types of NPs activated the complement system primarily via the alternative pathway rather than the lectin pathway The classical pathway was activated to a very small extent by the NPs with carboxyl and amine surface groups. Human serum and plasma protein binding studies showed that these NPs had different protein binding patterns. Studies of both complement activation and coagulation activation suggested that NPs with methoxyl surface groups might be an ideal candidate for drug delivery applications, since they are not likely to cause any immunological adverse reaction in the human body

Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000’s. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers