The effect of comb length on the in vitro and in vivo properties of self-assembled poly(oligoethylene glycol methacrylate)-based block copolymer nanoparticles.

Comb copolymer analogues of poly(lactic acid)-polyethylene glycol block copolymers (PLA-b-PEG) offer potential to overcome the inherent chemistry and stability limitations of their linear block copolymer counterparts. Herein, we examine the differences between P(L)LA10K-b-PEG10K and linear-comb copolymer analogues thereof in which the linear PEG block is replaced by poly(oligo(ethylene glycol) methacrylate) (POEGMA) blocks with different side chain (comb) lengths but the same overall molecular weight. P(L)LA10K-b-POEGMA47510K and P(L)LA10K-b-POEGMA200010K block copolymers were synthesized via activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and fabricated into self-assembled nanoparticles using flash nanoprecipitation via confined impinging jet mixing. Linear-comb copolymer analogues based on PLA-b-POEGMA yielded smaller but still well-controlled nanoparticle sizes (88 ± 2 nm and 114 ± 1 nm respectively compared to 159 ± 2 nm for P(L)LA10K-b-PEG10K nanoparticles) that exhibited improved colloidal stability relative to linear copolymer-based nanoparticles over a 15 day incubation period while maintaining comparably high cytocompatibility, although the comb copolymer analogues had somewhat lower loading capacity for doxorubicin hydrochloride. Cell spheroid studies showed that the linear-comb copolymers promoted enhanced tumor transport and thus cell killing compared to conventional linear block copolymers. In vivo studies showed all NP types could passively accumulate within implanted CT26 tumors but with different accumulation profiles, with P(L)LA10K-b-POEGMA200010K NPs showing continuous accumulation throughout the full 24 h monitoring period whereas tumor accumulation of P(L)LA10K-b-POEGMA47510K NPs was significant only between 8 h and 24 h. Overall, the linear-comb copolymer analogues exhibited superior stability, biodistribution, spheroid penetration, and inherent tunability over linear NP counterparts.

Injectable and Dynamically Crosslinked Zwitterionic Hydrogels for Anti-Fouling and Tissue Regeneration Applications.

A zwitterionic injectable and degradable hydrogel based on hydrazide and aldehyde-functionalized [2-(methacryloyloxy)ethyl] dimethyl-(3-sulfopropyl)ammonium hydroxide (DMAPS) precursor polymers that can address practical in vivo needs is reported. Zwitterion fusion interactions between the zwitterionic precursor polymers create a secondary physically crosslinked network to enable much more rapid gelation than previously reported with other synthetic polymers, facilitating rapid gelation at much lower polymer concentrations or degrees of functionalization than previously accessible in addition to promoting zero swelling and long-term degradation responses and significantly stiffer mechanics than are typically accessed with previously reported low-viscosity precursor gelation systems. The hydrogels maintain the highly anti-fouling properties of conventional zwitterionic hydrogels against proteins, mammalian cells, and bacteria while also promoting anti-fibrotic tissue responses in vivo. Furthermore, the use of the hydrogels for effective delivery and subsequent controlled release of viable cells with tunable profiles both in vitro and in vivo is demonstrated, including the delivery of myoblasts in a mouse skeletal muscle defect model for reducing the time between injury and functional mobility recovery. The combination of the injectability, degradability, and tissue compatibility achieved offers the potential to expand the utility of zwitterionic hydrogels in minimally invasive therapeutic applications.

A Nanocomposite Dynamic Covalent Cross-Linked Hydrogel Loaded with Fusidic Acid for Treating Antibiotic-Resistant Infected Wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high levels of morbidity and is considered a difficult-to-treat infection, often requiring nonstandard treatment regimens and antibiotics. Since over 40% of the emerging antibiotic compounds have insufficient solubility that limits their bioavailability and thus efficacy through oral or intravenous administration, it is crucial that alternative drug delivery products be developed for wound care applications. Existing effective treatments for soft tissue MRSA infections, such as fusidic acid (FA), which is typically administered orally, could also benefit from alternative routes of administration to improve local efficacy and bioavailability while reducing the required therapeutic dose. Herein, we report an antimicrobial poly(oligoethylene glycol methacrylate) (POEGMA)-based composite hydrogel loaded with fusidic acid-encapsulating self-assembled polylactic acid-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (PLA-POEGMA) nanoparticles for the treatment of MRSA-infected skin wounds. The inclusion of the self-assembled nanoparticles (380 nm diameter when loaded with fusidic acid) does not alter the favorable mechanical properties and stability of the hydrogel in the context of its use as a wound dressing, while fusidic acid (FA) can be released from the hydrogel over ∼10 h via a diffusion-controlled mechanism. The antimicrobial studies demonstrate a clear zone of inhibition in vitro and a 1-2 order of magnitude inhibition of bacterial growth in vivo in an MRSA-infected full-thickness excisional murine wound model even at very low antibiotic doses. Our approach thus can both circumvent challenges in the local delivery of hydrophobic antimicrobial compounds and directly deliver antimicrobials into the wound to effectively combat methicillin-resistant infections using a fraction of the drug dose required using other clinically relevant strategies.

Disulfide-Cross-Linked Nanogel-Based Nanoassemblies for Chemotherapeutic Drug Delivery.

Although nanoparticle-based chemotherapeutic strategies have gained in popularity, the efficacy of such therapies is still limited in part due to the different nanoparticle sizes needed to best accommodate different parts of the drug delivery pathway. Herein, we describe a nanogel-based nanoassembly based on the entrapment of ultrasmall starch nanoparticles (size 10-40 nm) within disulfide-crosslinked chondroitin sulfate-based nanogels (size 150-250 nm) to address this challenge. Upon exposure of the nanoassembly to the reductive tumor microenvironment, the chondroitin sulfate-based nanogel can degrade to release the doxorubicin-loaded starch nanoparticles in the tumor to facilitate improved intratumoral penetration. CT26 colon carcinoma spheroids could be efficiently penetrated by the nanoassembly (resulting in 1 order of magnitude higher DOX-derived fluorescence inside the spheroid relative to free DOX), while in vivo experiments showed that doxorubicin-loaded nanoassemblies reduced tumor sizes by 6× relative to saline controls and 2× relative to free DOX after 21 days. Together, these data suggest that nanogel-based nanoassemblies are a viable option for improving the efficacy and safety of nanoparticle-based drug delivery vehicles treating cancer.

Using the Intranasal Route to Administer Drugs to Treat Neurological and Psychiatric Illnesses: Rationale, Successes, and Future Needs.

While the intranasal administration of drugs to the brain has been gaining both research attention and regulatory success over the past several years, key fundamental and translational challenges remain to fully leveraging the promise of this drug delivery pathway for improving the treatment of various neurological and psychiatric illnesses. In response, this review highlights the current state of understanding of the nose-to-brain drug delivery pathway and how both biological and clinical barriers to drug transport using the pathway can been addressed, as illustrated by demonstrations of how currently approved intranasal sprays leverage these pathways to enable the design of successful therapies. Moving forward, aiming to better exploit the understanding of this fundamental pathway, we also outline the development of nanoparticle systems that show improvement in delivering approved drugs to the brain and how engineered nanoparticle formulations could aid in breakthroughs in terms of delivering emerging drugs and therapeutics while avoiding systemic adverse effects.

Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy.

Multiple biological barriers must be considered in the design of nanomedicines, including prolonged blood circulation, efficient accumulation at the target site, effective penetration into the target tissue, selective uptake of the nanoparticles into target cells, and successful endosomal escape. However, different particle sizes, surface chemistries, and sometimes shapes are required to achieve the desired transport properties at each step of the delivery process. In response, this review highlights recent developments in the design of switchable nanoparticles whose size, surface chemistry, shape, or a combination thereof can be altered as a function of time, a disease-specific microenvironment, and/or via an externally applied stimulus to enable improved optimization of nanoparticle properties in each step of the delivery process. The practical use of such nanoparticles in chemotherapy, bioimaging, photothermal therapy, and other applications is also discussed.

In situ-gelling starch nanoparticle (SNP)/O-carboxymethyl chitosan (CMCh) nanoparticle network hydrogels for the intranasal delivery of an antipsychotic peptide.

Existing oral or injectable antipsychotic drug delivery strategies typically demonstrate low bioavailability to targeted brain regions, incentivizing the development of alternative delivery strategies. Delivery via the nasal cavity circumvents multiple barriers for reaching the brain but requires drug delivery vehicles with very specific properties to be effective. Herein, we report in situ-gelling and degradable bulk nanoparticle network hydrogels consisting of oxidized starch nanoparticles (SNPs) and carboxymethyl chitosan (CMCh) that enable intranasal delivery via spray, high nasal mucosal retention, and functional controlled release of the peptide drug PAOPA, a positive allosteric modulator of dopamine D2 receptor. PAOPA-loaded SNP-CMCh hydrogels can alleviate negative symptoms like behavioural abnormalities associated with schizophrenia (i.e. decreased social interaction time) for up to 72 h in an MK-801-induced pre-clinical rat model of schizophrenia at a low drug dosage (0.5 mg/kg); in comparison, conventional PAOPA administration via the intraperitoneal route requires twice the PAOPA dose to achieve a therapeutic effect that persists for only a few hours. This strategy offers potential for substantially decreasing re-administration frequencies and overall drug doses (and thus side-effects) of a range of potential antipsychotic drugs via a minimally-invasive administration route.