Thermal and pH Sensitive Composite Membrane for On-Demand Drug Delivery by Applying an Alternating Magnetic Field

Implantable drug delivery systems that can realize a scheduled drug release according to the needs of patients would be highly beneficial for the treatment of chronic diseases and cancer. Here, micrometer‐sized hydrogel particles with both thermal and pH sensitivities are fabricated for the first time and embedded with magnetic nanoparticles in silk fibroin to generate a composite membrane. The permeability of the membrane is adjustable reversibly by temperature and pH. Promptly responded drug release within 1 min by applying an alternating magnetic field is demonstrated with the membrane. The on/off switching of an alternating magnetic field (16 mT, 111 kHz) induces heat generation by the magnetic nanoparticles resulting in a reversible change of the membrane permeability due to the shrinking/swelling of the microgels. A control over two orders of magnitude of the release rate (0.01–5.0 µg min−1) of Rhodamine B (Rh.B) model drug is achieved by tuning the content of microgels and magnetic nanoparticles, as well as the thickness of the membrane. Additionally, an increase in the release rate of Rh.B in acidic condition with respect to the physiological pH value is demonstrated. This represents an additional functionality of the implantable membrane with relevant features for spatially selective cancer treatment.

Magnetic nanoparticle-induced hyperthermia with appropriate payloads: Paul Ehrlich's "magic (nano)bullet" for cancer theranostics?

Heinrich Hofmann, Swati Krishnan

Effective multimodal cancer management requires the optimal integration of diagnostic and therapeutic modalities. Radiation therapy, chemotherapy and immunotherapy, alone or in combination, are integral parts of various cancer treatment protocols. Hyperthermia at 39-45 degrees C is a potent radiosensitiser and has been shown to improve therapeutic outcomes in various tumours through its synergy with chemotherapy. Gene silencing approaches, using small interfering RNAs and microRNAs, are also being explored in clinical trials in oncology. The rapid developments in multifunctional nanoparticles provide ample opportunities to integrate both diagnostic and therapeutic modalities into a single effective cancer "theranostic" vector. Nanoparticles could extravasate passively into the tumour tissues in preference to the adjacent normal tissues by capitalizing on the enhanced permeability and retention effect. Tumour targeting might be further augmented by conjugating tumour-specific peptides and antibodies onto the surface of these nanoparticles or by activation through electromagnetic radiations, laser or ultrasound. Magnetic nanoparticles can induce hyperthermia in the presence of an alternating magnetic field, thereby multifunctionally with tumour-specific payloads empowering tumour specific radiotheranostics (for both imaging and radiotherapy), chemotherapy drug delivery, immunotherapy and gene silencing therapy. Such a (nano)bullet could realise the "magic bullet" conceived by Paul Ehrlich more than a century ago. This article discusses the various aspects of this "magic (nano)bullet" and the challenges that need to be addressed to usher in this new paradigm in modern cancer diagnostics and therapeutics. (C) 2016 Elsevier Ltd. All rights reserved.

Elsevier2016

Thermal Responsive Silk Composite Membrane for Magnetic Field Triggered Controllable Drug Delivery

Ya Wang

Drug delivery implant which provides localized and controlled drug release is beneficial for the therapies of chronic diseases and tumors. This dissertation aims to develop thermal responsive composite membranes that can be utilized as smart drug release implants. Magnetic field is chosen as the external trigger due to its harmlessness and spatio-temporal control. A fully biodegradable composite membrane is prepared to prevent the risk of secondary damages caused by surgery to take out non-biodegradable implants after the treatment. The membrane is made from silk fibroin and MNPs, and its stability in water can be prolonged up to several months by increasing the content of ß-sheet structures through ethanol annealing. The thermal degradation of the composite membrane starts consistently at around 200 °C, which is independent of membrane thickness, ethanol post-processing, and the existence of magnetic nanoparticles. The membrane can be remotely triggered by an alternating magnetic field (16 mT, 111 kHz) to open nanopores inside, through which a liquid can then diffuse. The controllable release of the Rhodamine B (Rh.B) model drug is achieved by adjusting the exposure time to the magnetic field. A longer exposure time, which results in more nanopore sites, increases the release rate eventually. Another composite membrane consisting of silk fibroin, MNPs, and poly(N-isopropylacrylamide) (PNIPAM) microgels (MGs) is prepared to be utilized as on-demand drug delivery implant, which can realize repeated, multiple releases according to the real-time needs of patients. PNIPAM-based thermal and pH dual sensitive microgel particles are fabricated by copolymerization of three monomers including N-isopropylacrylamide, isopropylmethacrylamide, and methacrylic acid. The dried microgels are uniform spheres with core-shell structures, and the diameter is around 1 µm with a core diameter of 800 nm and shell thickness of 160 nm respectively. It has been found that the microgel shrinks when the temperature increases, whereby its volume phase transition temperature (VPTT) depends also on the pH value. Both parameters are adjusted to be in the physiological relevant window. The measured VPTT is around 38 °C at pH 5.0 and increases to 44 °C at pH 7.4. The controlled release of the Rh.B model drug has been shown by changing the environmental temperature or pH. With higher temperature and more acidic pH, the release rate is faster. Additionally, a higher content of MGs and smaller thickness of the membrane facilitate the release of Rh.B. Furthermore, an alternating magnetic field of 16 mT at 111 kHz is applied to trigger the release of Rh.B remotely. The on/off switching of the magnetic field induces the shrinking/swelling of the microgels, changes reversibly the membrane permeability, and precisely controls the release of the model drug. A control over two orders of magnitude of the release rate (0.01 to 5.0 µg min-1) is achieved by tuning the content of microgels and magnetic nanoparticles, and the thickness of the membrane. In addition, it is found that a higher content of magnetic nanoparticles and a larger thickness contribute to a faster release rate of Rh.B due to the higher heating efficiency. Lastly, the observed much higher release rate of Rh.B in the acidic condition with respect to the physiological one represents a potentially important feature for spatially selective treatment of cancer.

EPFL2020

Thermal Responsive Silk Composite Membrane for Magnetic Field Triggered Controllable Drug Delivery

Ya Wang

EPFL2020