Most of the current nanoparticle-based therapeutics worldwide failing in clinical trials face three major challenges: (i) lack of an optimum drug delivery platform with precise composition, (ii) lack of a method of directly monitoring the fate of a specific drug rather than using any other labelling molecules as a compromise, and (iii) lack of reliable cancer models with high fidelity for drug screen and evaluation. Here, starting from a PP2A inhibitor demethylcantharidin (DMC) and cisplatin, the design of a dual sensitive dual drug backboned shattering polymer (DDBSP) with exact composition at a fixed DMC/Pt ratio for precise nanomedicine is shown. DDBSP self-assembled nanoparticle (DD-NP) can be triggered intracellularly to break down in a chain-shattering manner to release the dual drugs payload. Moreover, DD-NP with extremely high Pt heavy metal content in the polymer chain can directly track the drug itself via Pt-based drug-mediated computer tomography and ICP-MS both in vitro and in vivo. Finally, DD-NP is used to eradicate the tumor burden on a high-fidelity patient-derived lung cancer model for the first time.
Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These DOX@PLMB nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that DOX@PLMB nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.
The blood−brain barrier (BBB) is highly selective and acts as the interface between the central nervous system and circulation. While the BBB is critical for maintaining brain homeostasis, it represents a formidable challenge for drug delivery.Here we synthesized gold nanoparticles (AuNPs) for targeting the tight junction specifically and demonstrated that transcranial picosecond laser stimulation of these AuNPs post intravenous injection increases the BBB permeability. The BBB permeability change can be graded by laser intensity, is entirely reversible, and involves increased paracellular diffusion. BBB modulation does not lead to significant disruption in the spontaneous vasomotion or the structure of the neurovascular unit. This strategy allows the entry of immunoglobulins and viral gene therapy vectors, as well as cargoladen liposomes. We anticipate this nanotechnology to be useful for tissue regions that are accessible to light or fiberoptic application and to open new avenues for drug screening and therapeutic interventions in the central nervous system.
Precise manipulation of protein activity in living systems has broad applications in biomedical sciences. However, it is challenging to use light to manipulate protein activity in living systems without genetic modification. Here, we report a technique to optically switch off protein activity in living cells with high spatiotemporal resolution, referred to as molecular hyperthermia (MH). MH is based on the nanoscale-confined heating of plasmonic gold nanoparticles by short laser pulses to unfold and photoinactivate targeted proteins of interest. First, we show that protease-activated receptor 2 (PAR2), a Gprotein-coupled receptor and an important pathway that leads to pain sensitization, can be photoinactivated in situ by MH without compromising cell proliferation. PAR2 activity can be switched off in laser-targeted cells without affecting surrounding cells. Furthermore, we demonstrate the molecular specificity of MH by inactivating PAR2 while leaving other receptors intact. Second, we demonstrate that the photoinactivation of a tight junction protein in brain endothelial monolayers leads to a reversible blood−brain barrier opening in vitro. Lastly, the protein inactivation by MH is below the nanobubble generation threshold and thus is predominantly due to the nanoscale heating. MH is distinct from traditional hyperthermia (that induces global tissue heating) in both its time and length scales: nanoseconds versus seconds, nanometers versus millimeters. Our results demonstrate that MH enables selective and remote manipulation of protein activity and cellular behavior without genetic modification. KEYWORDS: plasmonic nanoparticle, nanosecond laser, protein inactivation, G-protein-coupled receptor, blood−brain barrier S elective and remote manipulation of protein function in living systems is important to elucidate the protein function and develop precise therapeutics for disease treatment. Advances in tool development have made
Carboranes with rich boron content have showed significant applications in the field of boron neutron capture therapy. Biodegradable derivatives of carborane-conjugated polymers with well-defined structure and tunable loading of boron atoms are far less explored. Herein, a new family of amphiphilic carborane-conjugated polycarbonates was synthesized by ring-opening polymerization of a carborane-installed cyclic carbonate monomer. Catalyzed by TBD from a poly(ethylene glycol) macroinitiator, the polymerization proceeded to relatively high conversions (>65%), with low polydispersity in a certain range of molecular weight. The boron content was readily tuned by the feed ratio of the monomer and initiator. The resultant amphiphilic polycarbonates self-assembled in water into spherical nanoparticles of different sizes depending on the hydrophilic-to-hydrophobic ratio. It was demonstrated that larger nanoparticles (PN150) were more easily subjected to protein adsorption and captured by the liver, and smaller nanoparticles (PN50) were more likely to enter cancer cells and accumulate at the tumor site. PN50 with thermal neutron irradiation exhibited the highest therapeutic efficacy in vivo. The new synthetic method utilizing amphiphilic biodegradable boron-enriched polymers is useful for developing more-selective and -effective boron delivery systems for BNCT.
Remote and minimally‐invasive modulation of biological systems with light has transformed modern biology and neuroscience. However, light absorption and scattering significantly prevents penetration to deep brain regions. Herein, we describe the use of gold‐coated mechanoresponsive nanovesicles, which consist of liposomes made from the artificial phospholipid Rad‐PC‐Rad as a tool for the delivery of bioactive molecules into brain tissue. Near‐infrared picosecond laser pulses activated the gold‐coating on the surface of nanovesicles, creating nanomechanical stress and leading to near‐complete vesicle cargo release in sub‐seconds. Compared to natural phospholipid liposomes, the photo‐release was possible at 40 times lower laser energy. This high photosensitivity enables photorelease of molecules down to a depth of 4 mm in mouse brain. This promising tool provides a versatile platform to optically release functional molecules to modulate brain circuits.
Neuropeptides are abundant signaling molecules in the central nervous system. Yet remarkably little is known about their spatiotemporal spread and biological activity. Here, we developed an integrated optical approach using Plasmonic nAnovesicles and cellbased neurotransmitter fluorescent engineered reporter (CNiFER), or PACE, to probe neuropeptide signaling in the mouse neocortex. Small volumes (fL to pL) of exogenously supplied somatostatin-14 (SST) can be rapidly released under near-infrared light stimulation from nanovesicles implanted in the brain and detected by SST2 CNiFERs with nM sensitivity. Our measurements reveal reduced but synchronized SST transmission within 130 μm, and markedly smaller and delayed transmission at longer distances. These measurements enabled a quantitative estimation of the SST loss rate due to peptide degradation and binding. PACE offers a new tool for determining the spatiotemporal scales of neuropeptide volume transmission and signaling in the brain.
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