Updating radical ring-opening polymerisation of cyclic ketene acetals from synthesis to degradation

Radical ring-opening polymerisation (RROP) of cyclic ketene acetals (CKAs) has gained momentum as it yields polyesters as biodegradable polymers from a radical polymerisation. In order to advance the polymerisation, some of its major limitations were addressed in the research presented, focussing on the four mainly used CKAs in modern research on RROP. Monomer synthesis has been updated towards a cobalt/TMSCl-based system that was performed reliably on several monomers at room temperature. Calculations using the density functional theory (DFT) revealed that the ring-opening step is energetically hampered in comparison to a ring-retaining reaction, which explained the challenges faced to promote the ring-opening reaction. Higher molecular weights up to four times the values reached by thermally initiated polymerisation were obtained by exploiting UV light and ultrasound as alternative methods to facilitate the polymerisation. The reaction procedure also influenced thermal properties of the polymers, which in turn affected the enzymatic degradation of nanoparticles based on those polymers. Altogether, the present study offers a holistic update to enhance the RROP of CKAs

Pulsed laser deposition of thick BaHfO3-doped YBa 2Cu307-δ films on highly alloyed textured Ni-W tapes

YBa2Cu3O7-δ (YBCO) films with a thickness of up to 3 μm containing nano-sized BaHfO3 (BHO) have been grown on Y2O3/Y-stabilized ZrO2/CeO 2 buffered Ni-9at% W tapes by pulsed laser deposition (PLD). Structural characterization by means of X-ray diffraction confirmed that the YBCO layer grew epitaxial. A superconducting transition temperature T c of about 89 K with a transition width of 1 K was determined, decreasing with increasing BHO content. Critical current density in self-field and at 0.3 T increased with increasing dopant level

iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis

Self-Assembly of Amphiphilic Block Copolypeptoids - Micelles, Worms and Polymersomes (vol 6, 33491, 2016)

The Acknowledgements section in this Article is incomplete

Chemotactic synthetic vesicles: Design and applications in blood-brain barrier crossing

In recent years, scientists have created artificial microscopic and nanoscopic self-propelling particles, often referred to as nano- or microswimmers, capable of mimicking biological locomotion and taxis. This active diffusion enables the engineering of complex operations that so far have not been possible at the micro- and nanoscale. One of the most promising tasks is the ability to engineer nanocarriers that can autonomously navigate within tissues and organs, accessing nearly every site of the human body guided by endogenous chemical gradients. We report a fully synthetic, organic, nanoscopic system that exhibits attractive chemotaxis driven by enzymatic conversion of glucose. We achieve this by encapsulating glucose oxidase alone or in combination with catalase into nanoscopic and biocompatible asymmetric polymer vesicles (known as polymersomes). We show that these vesicles self-propel in response to an external gradient of glucose by inducing a slip velocity on their surface, which makes them move in an extremely sensitive way toward higher-concentration regions. We finally demonstrate that the chemotactic behavior of these nanoswimmers, in combination with LRP-1 (low-density lipoprotein receptor–related protein 1) targeting, enables a fourfold increase in penetration to the brain compared to nonchemotactic systems

Revisiting monomer synthesis and radical ring opening polymerization of dimethylated MDO towards biodegradable nanoparticles for enzymes

Radical ring opening polymerization is a powerful tool to achieve a polyester via radical polymerization. We used it to obtain a dimethylated version of poly(caprolactone) (PdmCL) from dimethylated MDO (DMMDO). First, we revisited monomer synthesis and achieved a milder synthetic protocol by introducing a cobalt-based catalyst. We also developed a new route towards DMMDO via a cyclic carbonate using the Petasis chemistry. Amphiphilic block-copolymers were then generated by free radical polymerization of DMMDO with a PEG-based macroinitiator. The resulting polyesters self-assembled into nanoparticles that were biodegradable as well as biocompatible. The nanoparticles proved to be an effective protective shell for an entrapped enzyme that was released upon degradation of the polyester by esterase. We are confident that our results will spur further research into block-copolymers resulting from RROP

A modular RNA delivery system comprising spherical nucleic acids built on endosome-escaping polymeric nanoparticles

Nucleic acid therapeutics require delivery systems to reach their targets. Key challenges to be overcome include avoidance of accumulation in cells of the mononuclear phagocyte system and escape from the endosomal pathway. Spherical nucleic acids (SNAs), in which a gold nanoparticle supports a corona of oligonucleotides, are promising carriers for nucleic acids with valuable properties including nuclease resistance, sequence-specific loading and control of receptor-mediated endocytosis. However, SNAs accumulate in the endosomal pathway and are thus vulnerable to lysosomal degradation or recycling exocytosis. Here, an alternative SNA core based on diblock copolymer PMPC25–PDPA72 is investigated. This pH-sensitive polymer self-assembles into vesicles with an intrinsic ability to escape endosomes via osmotic shock triggered by acidification-induced disassembly. DNA oligos conjugated to PMPC25–PDPA72 molecules form vesicles, or polymersomes, with DNA coronae on luminal and external surfaces. Nucleic acid cargoes or nucleic acid-tagged targeting moieties can be attached by hybridization to the coronal DNA. These polymeric SNAs are used to deliver siRNA duplexes against C9orf72, a genetic target with therapeutic potential for amyotrophic lateral sclerosis, to motor neuron-like cells. By attaching a neuron-specific targeting peptide to the PSNA corona, effective knock-down is achieved at doses of 2 particles per cell

Bottom-Up Evolution of Vesicles from Disks to High-Genus Polymersomes

Polymersomes are vesicles formed by the self-assembly of amphiphilic copolymers in water. They represent one of the most promising alternatives of natural vesicles as they add new possibilities in the amphiphiles' molecular engineering of aqueous compartments. Here we report the design of polymersomes using a bottom-up approach wherein self-assembly of amphiphilic copolymers poly(2-(methacryloyloxy) ethyl phosphorylcholine)-poly(2-(diisopropylamino) ethyl methacrylate) (PMPC-PDPA) into membranes is tuned using pH and temperature. We report evolution from disk micelles, to vesicles, to high-genus vesicles (vesicles with many holes), where each passage is controlled by pH switch or temperature. We show that the process can be rationalized, adapting membrane physics theories to disclose scaling principles that allow the estimation of minimal radius of vesiculation as well as chain entanglement and coupling. This approach allows us to generate nanoscale vesicles with genus from 0 to 70, which have been very elusive and difficult to control so far