Construction of disulfide containing redox-responsive polymeric nanomedicine.

Disulfide bonds (S-S) are widely found in chemistry, biology, and materials science. Polymer nanomaterials containing disulfide bonds with a variety of excellent properties have great potential as drug and gene delivery carriers. The disulfide bond can exist stably in extracellular environment, but upon entering cancer cells, it will undergo a sulfhydryl-disulfide bond exchange reaction with glutathione (GSH) in the cytoplasm, causing the disulfide bond cleavage. Therefore, polymeric nanomaterials containing disulfide bonds are promising in cancer treatment due to the elevated GSH concentration inside cancer cells. This review highlights various synthetic approaches to prepare disulfide containing redox-responsive polymeric nanomedicine, including synthesis of disulfide bonds containing polymers, construction of polymeric nanoparticle with shell or core crosslinked disulfide bonds, preparation of polymer-drug conjugates via disulfide linkers, and disulfide linked responsive payloads.

Morphologic Design of Silver-Bearing Sugar-Based Polymer Nanoparticles for Uroepithelial Cell Binding and Antimicrobial Delivery.

Platelet-like and cylindrical nanostructures from sugar-based polymers are designed to mimic the aspect ratio of bacteria and achieve uroepithelial cell binding and internalization, thereby improving their potential for local treatment of recurrent urinary tract infections. Polymer nanostructures, derived from amphiphilic block polymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline poly(l-lactide) segments, were constructed with morphologies that could be tuned to enhance uroepithelial cell binding. These nanoparticles exhibited negligible cytotoxicity, immunotoxicity, and cytokine adsorption, while also offering substantial silver cation loading capacity, extended release, and in vitro antimicrobial activity (as effective as free silver cations) against uropathogenic Escherichia coli. In comparison to spherical analogues, cylindrical and platelet-like nanostructures engaged in significantly higher association with uroepithelial cells, as measured by flow cytometry; despite their larger size, platelet-like nanostructures maintained the capacity for cell internalization. This work establishes initial evidence of degradable platelet-shaped nanostructures as versatile therapeutic carriers for treatment of epithelial infections.

A Tale of Drug-Carrier Optimization: Controlling Stimuli Sensitivity via Nanoparticle Hydrophobicity through Drug Loading.

Interactions between drug molecules, nanocarrier components, and surrounding media influence the properties and therapeutic efficacies of nanomedicines. In this study, we investigate the role that reversible covalent loading of a hydrophobic drug exerts on intra-nanoparticle physical properties and explore the utility of this payload control strategy for tuning the access of active agents and, thereby, the stimuli sensitivity of smart nanomaterials. Glutathione sensitivity was controlled via altering the degree of hydrophobic payload loading of disulfide-linked camptothecin-conjugated sugar-based nanomaterials. Increases in degrees of camptothecin conjugation (fCPT) decreased aqueous accessibility and reduced glutathione-triggered release. Although the lowest fCPT gave the fastest camptothecin release, it resulted in the lowest camptothecin concentration. Remarkably, the highest fCPT resulted in a 5.5-fold improved selectivity against cancer vs noncancerous cells. This work represents an advancement in drug carrier design by demonstrating the importance of controlling the amount of drug loading on the overall payload and its availability.

Exquisite Vesicular Nanomedicine by Paclitaxel Mediated Co-assembly with Camptothecin Prodrug.

We report that the self-assembly of drug amphiphiles, Evans blue conjugated camptothecin prodrug (EB-CPT), can be modulated by another anticancer drug paclitaxel (PTX), resulting in ultrahigh quality of nanovesicles (NVs) with uniform shape and diameters of around 80 nm with the EB-CPT:PTX weight ratio of 1:1, 1:2, and 1:3, denoted as ECX NVs. Significantly, the co-assembly of EB-CPT and PTX without adding other excipients has nearly 100 % drug loading efficiency (DLE) and ultrahigh drug loading content (DLC) of PTX alone of up to 72.3±1.7 wt % which, to our best knowledge, is among the highest level reported in literature. Moreover, the ECX NVs with the EB-CPT:PTX weight ratio of 1:2 showed remarkable combination index of 0.59 at a level of 50 % efficacy against HCT116 cells in vitro and greatly improved tumor inhibition effect in vivo compared with two clinically approved CPT- and PTX-based anticancer nanomedicines (Onivyde and Abraxane) individually and their combinations.

In Situ Production of Ag/Polymer Asymmetric Nanoparticles via a Powerful Light-Driven Technique.

As a rapid, controllable, and easily transferrable approach to the preparation of antimicrobial nanoparticle systems, a one-step, light-driven procedure was developed to produce asymmetric hybrid inorganic-organic nanoparticles (NPs) directly from a homogeneous Ag/polymer mixture. An amphiphilic triblock polymer was designed and synthesized to build biocompatible NPs, consisting of poly(ethylene oxide) (PEO), carboxylic acid-functionalized polyphosphoester (PPE), and poly(l-lactide) (PLLA). Unexpectedly, snowman-like asymmetric nanostructures were subsequently obtained by simply loading silver cations into the polymeric micelles together with purification via centrifugation. With an understanding of the chemistry of the asymmetric NP formation, a controllable preparation strategy was developed by applying UV irradiation. A morphology transition was observed by transmission electron microscopy over the UV irradiation time, from small silver NPs distributed inside the micelles into snowman-like asymmetric NPs, which hold promise for potential antimicrobial applications with their unique two-stage silver release profiles.

Hybrid Nanomedicine Fabricated from Photosensitizer-Terminated Metal-Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy.

During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2 -consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal-organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nanocarriers. By virtue of strain-promoted azide-alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O2 -depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT-induced and hypoxia-activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia-activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.

Minocycline and Silver Dual-Loaded Polyphosphoester-Based Nanoparticles for Treatment of Resistant Pseudomonas aeruginosa.

Pseudomonas aeruginosa has been detected in the lungs of ∼50% of patients with cystic fibrosis (CF), including 20% of adult CF patients. The majority of these adult patients harbor multi-drug resistant (MDR) strains, limiting the available treatment options. Silver has long been used as a broad-spectrum antimicrobial agent with a low incidence of resistance. Despite low toxicity, poor availability of silver cations mandates a high dosage to effectively eradicate infections. To address this shortcoming of silver, nanoparticles have been used as delivery devices to improve treatment outcomes. Furthermore, studies have demonstrated that synergistic combinations with careful dose calibrations and efficient delivery systems result in superior antimicrobial activity while avoiding potential side effects of both therapeutics. Here 4-epi-minocycline, a metabolite of minocycline, was identified as an active antimicrobial against P. aeruginosa using a high-throughput screen. The antimicrobial activities of 4-epi-minocycline, minocycline, and silver acetate against clinical isolates of P. aeruginosa obtained from CF patients were evaluated in vitro. Next, the synergistic activity of the silver/minocycline combination against P. aeruginosa isolates was investigated using checkerboard assays and identified with end-point colony forming unit determination assays. Finally, nanoparticles coloaded with minocycline and silver were evaluated in vitro for antimicrobial activity. The results demonstrated that both silver and minocycline are potent antimicrobials alone and that the combination allows a reduced dosage of both therapeutics to achieve the same antimicrobial effect. Furthermore, the proposed synergistic silver/minocycline combination can be coloaded into nanoparticles as a next-generation antibiotic to combat the threats presented by MDR pathogens.

A Catalase-Like Metal-Organic Framework Nanohybrid for O2 -Evolving Synergistic Chemoradiotherapy.

Tumor hypoxia, the "Achilles' heel" of current cancer therapies, is indispensable to drug resistance and poor therapeutic outcomes especially for radiotherapy. Here we propose an in situ catalytic oxygenation strategy in tumor using porphyrinic metal-organic framework (MOF)-gold nanoparticles (AuNPs) nanohybrid as a therapeutic platform to achieve O2 -evolving chemoradiotherapy. The AuNPs decorated on the surface of MOF effectively stabilize the nanocomposite and serve as radiosensitizers, whereas the MOF scaffold acts as a container to encapsulate chemotherapeutic drug doxorubicin. In vitro and in vivo studies verify that the catalase-like nanohybrid significantly enhances the radiotherapy effect, alleviating tumor hypoxia and achieving synergistic anticancer efficacy. This hybrid nanomaterial remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theranostic nanomedicines.

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity.

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases.

Supramolecular Polymer-Based Nanomedicine: High Therapeutic Performance and Negligible Long-Term Immunotoxicity.

Nanomedicines have achieved several breakthroughs in cancer treatment over the past decades; however, their potential immunotoxicities are ignored, which results in serious adverse effects and greatly reduces the potential in clinical translation. Herein, we innovatively develop a theranostic supramolecular polymer using ß-cyclodextrin as the host and camptothecin (CPT) as the guest linked by a glutathione-cleavable disulfide bond. The supramolecular polymerization remarkably increases the solubility of CPT by a factor of 232 and effectively inhibits its lactone ring opening in physiological environment, which is favorable for intravenous formulation and maintenance of the therapeutic efficacy. Supramolecular nanoparticles can be prepared through orthogonal self-assembly driven by π-π stacking interaction, host-guest complexation, and hydrogen bonds. The sophisticated nanomedicine constructed from the obtained supramolecular polymer can be specifically delivered to tumor sites and rapidly excreted from body after drug release, thus effectively avoiding systemic toxicity, especially long-term immunotoxicity. In vivo investigations demonstrate this supramolecular nanomedicine possesses superior antitumor performance and antimetastasis capability. This pioneering example integrating the advantages of the dynamic nature of supramolecular chemistry and nanotechnology provides a promising platform for cancer theranostics.

Polymeric Nanoparticles with a Glutathione-Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy.

Polymeric micelle-based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)-sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co-deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α (HPPH) was conjugated via a GSH-cleavable linkage. The intrinsic fluorogenicity and label-free radio-chelation (64 Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP-loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP-based drug delivery.

Activatable Singlet Oxygen Generation from Lipid Hydroperoxide Nanoparticles for Cancer Therapy.

Reactive oxygen species (ROS)-induced apoptosis is a widely practiced strategy for cancer therapy. Although photodynamic therapy (PDT) takes advantage of the spatial-temporal control of ROS generation, the meticulous participation of light, photosensitizer, and oxygen greatly hinders the broad application of PDT as a first-line cancer treatment option. An activatable system has been developed that enables tumor-specific singlet oxygen (1 O2 ) generation for cancer therapy, based on a Fenton-like reaction between linoleic acid hydroperoxide (LAHP) tethered on iron oxide nanoparticles (IO NPs) and the released iron(II) ions from IO NPs under acidic-pH condition. The IO-LAHP NPs are able to induce efficient apoptotic cancer cell death both in vitro and in vivo through tumor-specific 1 O2 generation and subsequent ROS mediated mechanism. This study demonstrates the effectiveness of modulating biochemical reactions as a ROS source to exert cancer death.

Double-Layered Plasmonic-Magnetic Vesicles by Self-Assembly of Janus Amphiphilic Gold-Iron(II,III) Oxide Nanoparticles.

Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3 O4 NPs grafted with polymer brushes of different hydrophilicity on Au and Fe3 O4 surfaces separately. Like liposomes, the vesicle shell is composed of two layers of Au-Fe3 O4 NPs in opposite direction, and the orientation of Au or Fe3 O4 in the shell can be well controlled by exploiting the amphiphilic property of the two types of polymers.

Hierarchical Assembly of Bioactive Amphiphilic Molecule Pairs into Supramolecular Nanofibril Self-Supportive Scaffolds for Stem Cell Differentiation.

Molecular design of biomaterials with unique features recapitulating nature's niche to influence biological activities has been a prolific area of investigation in chemistry and material science. The extracellular matrix (ECM) provides a wealth of bioactive molecules in supporting cell proliferation, migration, and differentiation. The well-patterned fibril and intertwining architecture of the ECM profoundly influences cell behavior and development. Inspired by those features from the ECM, we attempted to integrate essential biological factors from the ECM to design bioactive molecules to construct artificial self-supportive ECM mimics to advance stem cell culture. The synthesized biomimic molecules are able to hierarchically self-assemble into nanofibril hydrogels in physiological buffer driven by cooperative effects of electrostatic interaction, van der Waals forces, and intermolecular hydrogen bonds. In addition, the hydrogel is designed to be degradable during cell culture, generating extra space to facilitate cell migration, expansion, and differentiation. We exploited the bioactive hydrogel as a growth-factor-free scaffold to support and accelerate neural stem cell adhesion, proliferation, and differentiation into functional neurons. Our study is a successful attempt to entirely use bioactive molecules for bottom-up self-assembly of new biomaterials mimicking the ECM to directly impact cell behaviors. Our strategy provides a new avenue in biomaterial design to advance tissue engineering and cell delivery.

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

Holistic assessment of covalently labeled core-shell polymeric nanoparticles with fluorescent contrast agents for theranostic applications.

The successful development of degradable polymeric nanostructures as optical probes for use in nanotheranostic applications requires the intelligent design of materials such that their surface response, degradation, drug delivery, and imaging properties are all optimized. In the case of imaging, optimization must result in materials that allow differentiation between unbound optical contrast agents and labeled polymeric materials as they undergo degradation. In this study, we have shown that use of traditional electrophoretic gel-plate assays for the determination of the purity of dye-conjugated degradable nanoparticles is limited by polymer degradation characteristics. To overcome these limitations, we have outlined a holistic approach to evaluating dye and peptide-polymer nanoparticle conjugation by utilizing steady-state fluorescence, anisotropy, and emission and anisotropy lifetime decay profiles, through which nanoparticle-dye binding can be assessed independently of perturbations, such as those presented during the execution of electrolyte gel-based assays. This approach has been demonstrated to provide an overall understanding of the spectral signature-structure-function relationship, ascertaining key information on interactions between the fluorophore, polymer, and solvent components that have a direct and measurable impact on the emissive properties of the optical probe. The use of these powerful techniques provides feedback that can be utilized to improve nanotheranostics by evaluating dye emissivity in degradable nanotheranostic systems, which has become increasingly important as modern platforms transition to architectures intentionally reliant on degradation and built-in environmental responses.

Development of polypeptide-based materials toward messenger RNA delivery.

Messenger RNA (mRNA)-based therapeutic agents have demonstrated significant potential in recent times, particularly in the context of the COVID-19 pandemic outbreak. As a promising prophylactic and therapeutic strategy, polypeptide-based mRNA delivery systems attract significant interest because of their low cost, simple preparation, tuneable sizes and morphology, convenient large-scale production, biocompatibility, and biodegradability. In this review, we begin with a brief discussion of the synthesis of polypeptides, followed by a review of commonly used polypeptides in mRNA delivery, including classical polypeptides and cell-penetrating peptides. Then, the challenges against mRNA delivery, including extracellular, intracellular, and clinical barriers, are discussed in detail. Finally, we highlight a range of strategies for polypeptide-based mRNA delivery, offering valuable insights into the advancement of polypeptide-based mRNA carrier development.

Tuneable redox-responsive albumin-hitchhiking drug delivery to tumours for cancer treatment.

This paper outlines a novel drug delivery system for highly cytotoxic mertansine (DM1) by conjugating to an albumin-binding Evans blue (EB) moiety through a tuneable responsive disulfide linker, providing valuable insights for the development of effective drug delivery systems toward cancer therapy.

Gene Transfection Efficiency Improvement with Lipid Conjugated Cationic Carbon Dots.

An ideal vehicle with a high transfection efficiency is crucial for gene delivery. In this study, a type of cationic carbon dot (CCD) known as APCDs were first prepared with arginine (Arg) and pentaethylenehexamine (PEHA) as precursors and conjugated with oleic acid (OA) for gene delivery. By tuning the mass ratio of APCDs to OA, APCDs-OA conjugates, namely, APCDs-0.5OA, APCDs-1.0OA, and APCDs-1.5OA were synthesized. All three amphiphilic APCDs-OA conjugates show high affinity to DNA through electrostatic interactions. APCDs-0.5OA exhibit strong binding with small interfering RNA (siRNA). After being internalized by Human Embryonic Kidney (HEK 293) and osteosarcoma (U2OS) cells, they could distribute in both the cytoplasm and the nucleus. With APCDs-OA conjugates as gene delivery vehicles, plasmid DNA (pDNA) that encodes the gene for the green fluorescence protein (GFP) can be successfully delivered in both HEK 293 and U2OS cells. The GFP expression levels mediated by APCDs-0.5OA and APCDs-1.0OA are ten times greater than that of PEI in HEK 293 cells. Furthermore, APCDs-0.5OA show prominent siRNA transfection efficiency, which is proven by the significantly downregulated expression of FANCA and FANCD2 proteins upon delivery of FANCA siRNA and FANCD2 siRNA into U2OS cells. In conclusion, our work demonstrates that conjugation of CCDs with a lipid structure such as OA significantly improves the gene transfection efficiency, providing a new idea about the designation of nonviral carriers in gene delivery systems.

Carbon dots as dual inhibitors of tau and amyloid-beta aggregation for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of senile dementia, presenting a significant challenge for the development of effective treatments. AD is characterized by extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Therefore, targeting both hallmarks through inhibition of amyloid beta (Aß) and tau aggregation presents a promising approach for drug development. Carbon dots (CD), with their high biocompatibility, minimal cytotoxicity, and blood-brain barrier (BBB) permeability, have emerged as promising drug nanocarriers. Congo red, an azo dye, has gathered significant attention for inhibiting amyloid-beta and tau aggregation. However, Congo red's inability to cross the BBB limits its potential to be used as a drug candidate for central nervous system (CNS) diseases. Furthermore, current studies only focus on using Congo red to target single disease hallmarks, without investigating dual inhibition capabilities. In this study, we synthesized Congo red-derived CD (CRCD) by using Congo red and citric acid as precursors, resulting in three variants, CRCD1, CRCD2 and CRCD3, based on different mass ratios of precursors. CRCD2 and CRCD3 exhibited sustained low cytotoxicity, and CRCD3 demonstrated the ability to traverse the BBB in a zebrafish model. Moreover, thioflavin T (ThT) aggregation assays and AFM imaging revealed CRCD as potent inhibitors against both tau and Aß aggregation. Notably, CRCD1 emerged as the most robust inhibitor, displaying IC50 values of 0.2 ± 0.1 and 2.1 ± 0.5 µg/mL against tau and Aß aggregation, respectively. Our findings underscore the dual inhibitory role of CRCD against tau and Aß aggregation, showcasing effective BBB penetration and positioning CRCD as potential nanodrugs and nanocarriers for the CNS. Hence, CRCD-based compounds represent a promising candidate in the realm of multi-functional AD therapeutics, offering an innovative formulation component for future developments in this area. STATEMENT OF SIGNIFICANCE: This article reports Congo red-derived carbon dots (CRCD) as dual inhibitors of tau and amyloid-beta (Aß) aggregation for the treatment of Alzheimer's disease (AD). The CRCD are biocompatible and show strong fluorescence, high stability, the ability to cross the blood-brain barrier, and the function of addressing two major pathological features of AD.