Comparative Effectiveness of Supervised and Home-Based Rehabilitation after Anterior Cruciate Ligament Reconstruction in Competitive Athletes.

After the increasingly common anterior cruciate ligament reconstruction (ACLR) procedure in competitive athletes, rehabilitation is crucial for facilitating a timely return to sports (RTS) and preventing re-injury. This pilot study investigates the patient-reported outcomes of postoperative rehabilitation in competitive athletes, comparing supervised rehabilitation (SVR) and home-based rehabilitation (HBR). After ACLR, 60 (out of 74 screened) athletes were recruited and equally divided into HBR and SVR groups using non-probability convenience sampling, with each group comprising 15 males and 15 females.

PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery.

Polyethyleneimine (PEI) has been extensively investigated as an efficient carrier for nucleic acid delivery. Yet, it suffers from a high toxicity profile that hinders clinical translation. Fluorination has proven to be a valid approach to reduce the cytotoxicity of PEI and improve the in vitro siRNA delivery potency.

Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization.

Stimuli-responsive nanogels are important drug and gene carriers that mediate the controlled release of therapeutic molecules. Herein, we report the synthesis of fully degradable disulfide cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2'-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA). Because the poly(EDDET) backbone repeat structure and cross-linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells.

Development of Cationic Quaternary Ammonium Sulfonamide Amino Lipids for Nucleic Acid Delivery.

Lipid nanoparticles (LNPs) currently comprise the most effective carrier class for the delivery of small RNAs. Among lipid carriers, charge-unbalanced lipids are relatively unexplored synthetically. Herein, we developed and evaluated a novel collection of compounds for small interfering RNA (siRNA) delivery, termed cationic quaternary ammonium sulfonamide amino lipids (CSALs).

Release mechanism of doxazosin from carrageenan matrix tablets: Effect of ionic strength and addition of sodium dodecyl sulphate.

The polyelectrolyte matrix tablets loaded with an oppositely charged drug exhibit complex drug-release mechanisms. In this study, the release mechanism of a cationic drug doxazosin mesylate (DM) from matrix tablets based on an anionic polyelectrolyte λ-carrageenan (λ-CARR) is investigated. The drug release rates from λ-CARR matrices are correlated with binding results based on potentiometric measurements using the DM ion-sensitive membrane electrode and with molecular characteristics of the DM-λ-CARR-complex particles through hydrodynamic size measurements.

Design of Poly-l-Glutamate-Based Complexes for pDNA Delivery.

Due to the polyanionic nature of DNA, typically cationic or neutral delivery vehicles have been used for gene delivery. As a new approach, this study focuses on the design, development, and validation of nonviral polypeptide-based carriers for oligonucleotide delivery based on a negatively charged poly-l-glutamic acid (PGA) backbone partly derivatized with oligoaminoamide residues. To this end, PGA-derivatives modified with different pentameric succinyl tetraethylene pentamines (Stp ) are designed.

Non-Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co-Delivery of Cas9 mRNA and sgRNA.

CRISPR/Cas is a revolutionary gene editing technology with wide-ranging utility. The safe, non-viral delivery of CRISPR/Cas components would greatly improve future therapeutic utility. We report the synthesis and development of zwitterionic amino lipids (ZALs) that are uniquely able to (co)deliver long RNAs including Cas9 mRNA and sgRNAs.

Intercalation-mediated nucleic acid nanoparticles for siRNA delivery.

Tremendous effort has been made to improve stability and delivery efficacy of small RNA therapeutics. However, nearly all current nano-encapsulation carriers utilize the critical balance between only two interacting parameters: RNA-binding electrostatic interactions and nanoparticle-stabilizing hydrophobic interactions. We report the development of intercalation-meditated nucleic acid (IMNA) nanoparticles, which utilize intercalation as a third interaction to enhance small RNA delivery.

Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient.

Activatable Water-Soluble Probes Enhance Tumor Imaging by Responding to Dysregulated pH and Exhibiting High Tumor-to-Liver Fluorescence Emission Contrast.

Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes that activate in response to pH are hindered by either fast clearance (in the case of small molecules) or high liver background emission (in the case of large particles). There remains a need to design water-soluble, long circulating, pH-responsive nanoprobes with high tumor-to-liver contrast.

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model.

RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations.

Combinatorial Optimization of Sequence-Defined Oligo(ethanamino)amides for Folate Receptor-Targeted pDNA and siRNA Delivery.

Cationic polymers present a versatile platform for the nonviral delivery of therapeutic nucleic acids. In order to achieve effective nucleic acid transfer, polymeric carriers ought to comprise multiple functionalities. Precise chemistries for site-specific placements of the different delivery modules within the carriers present the basis for uncovering structure-activity relationships required for further optimization.

Tumor Imaging Based on Photon Upconversion of Pt(II) Porphyrin Rhodamine Co-modified NIR Excitable Cellulose Enhanced by Aggregation.

We report a bioinspired upconversion (UC) system using a cellulose template, in which an aggregated platinum(II)-tetraphenylporphyrin (PtTPP) sensitizer is able to excite Rhodamine B as an emitter, enabling near-infrared (NIR)-to-orange wavelength conversions. The comodified cellulose was observed to undergo J aggregation of PtTPP in DMSO solution, as indicated by broad, weak absorption bands in the NIR region of the absorption spectrum. Excitation of these NIR J aggregation peaks of PtTPP led to efficient UC emission in the orange wavelength region.

Correction: biocompatible organic charge transfer complex nanoparticles based on a semi-crystalline cellulose template.

Correction for 'Biocompatible organic charge transfer complex nanoparticles based on a semi-crystalline cellulose template' by Atsushi Nagai et al., Chem. Commun.

Rapid Synthesis of a Lipocationic Polyester Library via Ring-Opening Polymerization of Functional Valerolactones for Efficacious siRNA Delivery.

The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Ring-opening polymerization of functional monomers has emerged as a versatile method to prepare clinically translatable degradable polyesters.1 A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive.

Biocompatible organic charge transfer complex nanoparticles based on a semi-crystalline cellulose template.

Using a bio-inspired cellulose template, new charge transfer (CT) nanoparticles (NPs) with unique and intriguing emission properties are reported. Pyrene-modified 2,3-di-O-methyl cellulose formed CT complexes with small molecule acceptors, e.g.

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer.

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses.

Combining polyethylenimine and Fe(III) for mediating pDNA transfection.

Background: The potential use of Fe(III) ions in biomedical applications may predict the interest of its combination with pDNA-PEI polyplexes. The present work aims at assessing the impact of this metal on pDNA complex properties.

Methods: Variations in the formation of complexes were imposed by using two types of biological buffers at different salt conditions.

Twin disulfides as opportunity for improving stability and transfection efficiency of oligoaminoethane polyplexes.

The synthesis of precise gene delivery vehicles by solid-supported chemistry is an effective way to establish structure-activity relationships and optimize existing transfection carriers. Sequence-defined cationic oligomers with different topologies were modified with twin disulfide-forming cysteine-arginine-cysteine (CRC) motifs. The influence of this motif versus single disulfide on the biophysical properties and biological performance of polyplexes was investigated, with pDNA and siRNA as nucleic acid cargoes.

Dual-targeted polyplexes based on sequence-defined peptide-PEG-oligoamino amides.

For active cell targeting, viruses frequently capitalize on dual-receptor binding. With the intention to mimic this natural process, a dual peptide-based approach for targeting cancer cells was evaluated. For this purpose, sequence-defined pDNA binding oligo (ethane amino) amides containing a PEG chain with a peptidic targeting ligand at its distal end were applied.

Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes.

The antifolate drug methotrexate (MTX) can serve as a dual-functional ligand in antitumoral drug delivery, inducing both a folate receptor mediated cellular uptake and an intracellular cytotoxic action. Bioactivity of MTX however changes by conjugation; the activity can be affected by the hampered intracellular conversion to more potent poly-γ-glutamyl derivatives. Therefore, in a cancer combination therapy approach for the codelivery of cytotoxic dsRNA polyinosinic-polycytidylic acid poly(I:C), a set of molecularly precise oligo(ethanamino)amides were synthesized comprising poly(ethylene glycol) conjugated MTX ligands.

Native chemical ligation for conversion of sequence-defined oligomers into targeted pDNA and siRNA carriers.

Native chemical ligation (NCL) was established for the conversion of sequence-defined oligomers of different topologies into targeted and PEG shielded pDNA and siRNA carriers. From an existing library of non-targeted oligoethanamino amides, six oligomers containing N-terminal cysteines were selected as cationic cores, to which monodisperse polyethylene glycol (PEG) containing terminal folic acid as targeting ligand (or terminal alanine as targeting negative control ligand) were attached by NCL. Ligated conjugates plus controls (in sum 18 oligomers) were evaluated for pDNA or siRNA gene delivery.

Gene regulation by intracellular delivery and photodegradation of nanoparticles containing small interfering RNA.

Although the use of small interfering RNA (siRNA) is a promising technique for gene regulation, spatiotemporal control of the effects of siRNA must be achieved if the technique is to be safe and practical. Here, a method for spatiotemporal regulation of genes with nanoparticles containing siRNA is reported. The siRNA is encapsulated in photodegradable nanoparticles that are internalized to SKOV3-Luc cells, where the siRNA is released from the nanoparticles by UV irradiation for 30 s.