Cyclodextrin Polymer-Loaded Micro-Ceramic Balls for Solid-Phase Extraction of Triazole Pesticides from Water.

A citric acid cross-linked ß-cyclodextrin (ß-CD) polymer was synthesized and loaded on micro-ceramic balls to fabricate the solid-phase adsorbents (P-MCB) for adsorption and extraction of triazole pesticides from water. The stability of ß-CD polymer and P-MCB was investigated in solutions with different pH values at different temperatures. The adsorption properties and the influence of kinetics, sorbent amount, pesticide concentration, and temperature on the adsorption capacity were evaluated. The results showed P-MCB had favorable adsorption of 15.98 mg/g flutriafol in 3.5 h. The equilibrium data followed the Freundlich equation, and the adsorption of flutriafol and diniconazole followed the second-order kinetics. The recovery rate of P-MCB for triazole pesticides in water was satisfactory, and the recovery rate was still 80.1%, even at the 10th cycle. The P-MCB had good stability, with a degradation rate of 0.2% ± 0.08 within 10 days, which could ensure extraction and recycling.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

PDT-Enhanced Ferroptosis by a Polymer Nanoparticle with pH-Activated Singlet Oxygen Generation and Superb Biocompatibility for Cancer Therapy.

In this study, we reported a nanocomplex (PAF) of PEGylated polygalacturonic acid, 5,10,15,20-tetrakis (4-aminophenyl) porphyrin (TAPP), and Fe3+ for photodynamic therapy (PDT)-enhanced ferroptosis in cancer treatment. PAF exhibited a size of 135 nm and a TAPP and Fe3+ loading content of 6.99 and 0.77%, respectively. The singlet oxygen (1O2) generation capacity of TAPP can be activated and significantly enhanced at acidic pH (4.5-5.0). Besides, the enhanced near-infrared absorption of TAPP at acidic pH enabled a further increase in 1O2 generation capability by a near-infrared laser (760 nm). The polysaccharide-based polymer carrier offers excellent biocompatibility, and PAF displayed a proliferative effect in both normal (L929) and cancer (B16) cells. However, upon light irradiation, PAF exhibited high toxicity to B16 melanoma cells by intracellular reactive oxygen species elevation, glutathione depletion, and lipid peroxidation. PAF displayed a much better anticancer effect than the nanocomplex containing Fe3+ or TAPP alone, indicating the PDT-enhanced ferroptosis in PAF. This study suggested that PDT-enhanced ferroptosis could be a facile and robust strategy of nanotherapeutics with high potency, tumor selectivity, and excellent biocompatibility.

Cinnamaldehyde-Based Poly(ester-thioacetal) To Generate Reactive Oxygen Species for Fabricating Reactive Oxygen Species-Responsive Nanoparticles.

Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA-HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles.

Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery.

With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 µg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 µg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.

A ROS-responsive polymeric micelle with a π-conjugated thioketal moiety for enhanced drug loading and efficient drug delivery.

As the implications of reactive oxygen species (ROS) are elucidated in many diseases, ROS-responsive nanoparticles are attracting great interest from researchers. In this work, a ROS sensitive thioketal (TK) moiety with a π-conjugated structure was introduced into biodegradable methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)mPEG-TK-PCL micelles as a linker, which was designed to speed up the drug release and thus enhance the therapeutic efficacy. The micelle showed a high drug loading content of 12.8% and excellent stability under physiological conditions because of the evocation of π-π stacking and hydrophobic interactions with the anticancer drug doxorubicin (DOX). The polymeric micelle presented a better drug carrier capacity and higher in vitro anticancer efficacy towards cancer cells. The in vivo study showed that DOX-loaded mPEG-TK-PCL micelles displayed lower toxicity towards normal cells and remarkably enhanced antitumor efficacy. This research provides a way to design potential drug carriers for efficient cancer chemotherapy.

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease.

Colonic epithelial damage and dysregulated immune response are crucial factors in the progression and exacerbation of inflammatory bowel disease (IBD). Nanoenabled targeted drug delivery to the inflamed intestinal mucosa has shown promise in inducing and maintaining colitis remission, while minimizing side effects. Inspired by the excellent antioxidative and anti-inflammatory efficacy of naturally derived magnolol (Mag) and gut homeostasis regulation of microbiota-derived butyrate, we developed a pH/redox dual-responsive butyrate-rich polymer nanoparticle (PSBA) as an oral Mag delivery system for combinational therapy of IBD. PSBA showed a high butyrate content of 22% and effectively encapsulated Mag. The Mag-loaded nanoparticles (PSBA@Mag) demonstrated colonic pH and reduction-responsive drug release, ensuring efficient retention and adhesion in the colon of colitis mice. PSBA@Mag not only normalized the level of reactive oxygen species and inflammatory effectors in inflamed colonic mucosa but also restored the epithelial barrier function in both ulcerative colitis and Crohn's disease mouse models. Importantly, PSBA promoted the migration and healing ability of intestinal epithelial cells in vitro and in vivo, sensitizing the therapeutic efficacy of Mag in animal models. Moreover, transcriptomics and metabolism analyses revealed that PSBA@Mag mitigated inflammation by suppressing the production of pro-inflammatory cytokines and chemokines and restoring the lipid metabolism. Additionally, this nanomedicine modulated the gut microbiota by inhibiting pathogenic Proteus and Escherichia-Shigella and promoting the proliferation of beneficial probiotics, including Lachnoclostridium, Lachnospiraceae_NK4A136_group and norank_f_Ruminococcaceae. Overall, our findings highlight the potential of butyrate-functionalized polymethacrylates as versatile and effective nanoplatforms for colonic drug delivery and mucosa repair in combating IBD and other gastrointestinal disorders.

Harnessing polymer-derived drug delivery systems for combating inflammatory bowel disease.

The inflammatory bowel disease (IBD) is incurable, chronic, recrudescent disorders in the inflamed intestines. Current clinic treatments are challenged by systemic exposure-induced severe side effects, inefficiency after long-term treatment, and increased risks of infection and malignancy due to immunosuppression. Fortunately, naturally bioactive small molecules, reactive oxygen species scavengers (or antioxidants), and gut microbiota modulators have emerged as promising candidates for the IBD treatment. Polymeric systems have been engineered as a delivery vehicle to improve the bioavailability and efficacy of these therapeutic agents through targeting the mucosa and enhancing intestinal adhesion and retention, and reduce their systemic toxicity. Herein we survey polymer-derived drug delivery systems for combating the IBD. Advanced delivery technologies, therapeutic intervention strategies, and the principles for the construction of hierarchical, mucosa-targeting, and bioresponsive systems are elaborated, providing insights into design and development of from-bench-to-bedside drug delivery polymeric systems for the IBD treatment.

A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy.

Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H2O2 and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.

A double-layer dura mater based on poly(caprolactone-co-lactide) film and polyurethane sponge: preparation, characterization, and biodegradation study.

Synthetic, biodegradable polymers hold great potential in dura mater substitution. In this study, a dura mater-mimetic double-layer film@sponge composite was developed. The composite contains a poly(caprolactone-co-lactide) (PCLA) film and polyurethane (PU) sponge, which simulates the hard and soft layers of dura mater, respectively. PCLA films were prepared by a solution-casting method and showed excellent mechanical properties and tolerance to water. PU sponge was hydrophilic and had a high water-absorption rate (about 500%). The double-layer composite (film@sponge) integrated the good mechanical properties of the films and the good water absorption of the sponge. The excellent biocompatibility and biodegradability of the PCLA film@PU sponge composites were verified by in vitro degradation and cytotoxicity study and the in vivo implantation in the back of rats. Importantly, the film@sponge composite had a suitable degradation rate and good biocompatibility, holding potential in the field of dural repair.

Thermosensitive polymer hydrogel as a physical shield on colonic mucosa for colitis treatment.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), is a chronic disease characterized by diffuse mucosal inflammation limited to the colon. Topical drug delivery systems that could be facilely performed and efficiently retained at colon sites are attractive for clinical IBD treatment. Herein, we report the exploration of an injectable thermosensitive copolymer hydrogel as a topical formulation for IBD treatment and demonstrate its feasibility in UC treatment by shielding ulcer sites from the external environment and being a drug reservoir for sustained release. Poly(aliphatic ester)-based triblock copolymer, poly(dl-lactic acid)-poly(ethylene glycol)-poly(dl-lactic acid) (PDLLA-PEG-PDLLA), adopts the solution state at room temperature yet a gel state at body temperature when the polymer concentration is more than 11%. The gel acts not only as a physical mucosal barrier for protecting ulcer sites from microorganisms like bacteria but also as a mesalazine depot for enhanced drug retention in the colon for localized, sustained drug release. In vivo UC treatment reveals that blank gel as a mucosal protector shows nearly the same treatment effect to mesalazine SR granules. Mesalazine-loaded gel significantly suppresses inflammation and has the best outcomes of indices such as colonic length, mucosal injury index, pathological tissue, and inflammatory factor. The injectable thermosensitive polymer hydrogel represents a novel, robust platform for the efficient treatment of IBD by acting as a physical shield to block out the pro-inflammatory factors as well as a drug depot for enhanced drug retention and controlled delivery.

Polymer Structure-Guided Self-Assisted Preparation of Poly(ester-thioether)-Based Hollow Porous Microspheres and Hierarchically Interconnected Microcages for Drug Release.

Porous polymer microspheres (PPMs) have been widely applied in various biomedical fields. Herein, the self-assisted preparation of poly(ester-thioether)-based porous microspheres and hierarchical microcages, whose pore sizes can be controlled by varying the polymer structures, is reported. Poly(ester-thioether)s with alkyl side chains (carbon atom numbers were 2, 4, and 8) can generate hollow porous microspheres; the longer alkyl chain length, the larger pore size of microspheres. The allyl-modified poly(ester-thioether) (PHBDT-g-C3 ) can form highly open, hierarchically interconnected microcages. A formation mechanism of these PPMs is proposed; the hydrophobic side chains-mediated stabilization of oil droplets dictate the droplet aggregation and following solvent evaporation, which is the key to the formation of PPMs. The hierarchically interconnected microcages of PHBDT-g-C3 are due to the partially crosslinking of polymers. Pore sizes of PPMs can be further tuned by a simple mixing strategy of poly(ester-thioether)s with different pore-forming abilities. The potential application of these PPMs as H2 O2 -responsive vehicles for delivery of hydrophobic (Nile Red) and hydrophilic (doxorubicin hydrochloride) cargos is also investigated. The microspheres with larger pore sizes show faster in vitro drug release. The poly(ester-thioether)-based polymer microspheres can open a new avenue for the design of PPMs and provide a H2 O2 -responsive drug delivery platform.

Polymeric nanoparticles responsive to intracellular ROS for anticancer drug delivery.

Thioketal and thioether are moieties used to fabricate reactive oxygen species (ROS)-responsive polymers for drug delivery. In this paper, three amphiphilic copolymers of mPEG-poly(ester-thioether), mPEG-poly(thioketal-ester) and mPEG-poly(thioketal-ester-thioether) were synthesized. The ROS-responsive behaviors of the three copolymers nanoparticles as drug carriers were investigated. The ROS-sensitivity was demonstrated by NMR, DLS, and SEM. mPEG-poly(ester-thioether) nanoparticles exhibited the fastest drug release rate, which possessed the best ROS sensitivity. The in vitro anticancer activity of the DOX-loaded nanoparticles was studied, the results revealed that the mPEG-poly(ester-thioether) nanoparticles showed the most efficient anticancer activity. Notably, all the three ROS-responsive copolymers nanoparticles showed enhanced cellular uptake and anticancer efficacy comparing to the control mPEG-b-PCL nanoparticles.

Effective combination therapy of percutaneous ethanol injection and chemotherapy based on injectable low molecular weight gels.

Percutaneous ethanol injection (PEI) therapy was used in liver cancer treatment, however, the therapeutic ethanol in PEI easily flew away from injected solid tumours and hinder the treatment effect. In this paper, injectable supramolecular gels formed by self-assembly of low molecular weight gelators (LMWGs) based on glycylglycine modified phenylboronic acid were prepared to localize ethanol and load chemotherapeutic drug for in situ synergistic therapy. The mechanism, morphology and rheological property of supramolecular gels were characterized by NMR, UV, SEM, etc. The rheological study revealed that the gels were formed in situ rapidly and recovered promptly once damaged. The gels were non-toxicity to both normal 3T3 fibroblasts cells and 4T1 breast cancer cells. Doxorubicin (DOX) hydrochloride and ethanol were encapsulated in the gels for the combination of chemotherapy and PEI therapy. The in vivo anticancer activity of the DOX-loaded gels was carried out in tumour bearing mice. The injected gels were coated around tumour tissues to lock ethanol, and DOX was released sustainingly from the gels to maintain effective concentration to induce the apoptosis of tumour cells. DOX-loaded gels and the ethanol exhibited excellent therapeutic efficacy and low side effects in local cancer therapy.

Fluorescence Resonance Energy Transfer Visualization of Molecular Delivery from Polymeric Micelles.

Polymeric micelles are important carriers for anticancer drug delivery. However, rare papers focused on the dynamic of drug in the core of micelles. In this paper, we used fluorescence resonance energy transfer (FRET) technique to investigate the dynamic diffusion of drug from polymeric micelles. mPEG-PCL diblock copolymers were used as carriers. A pair of fluorescence molecules Cy3 and Cy5 was selected to evoke the FRET phenomenon. Cy5 was immobilized on the terminal group of PCL segments, Cy3 was encapsulated in the Cy5 modified polymeric micelles as the model drug. The drug loaded polymeric micelles were incubated with 4T1 breast cancer cells. The FRET was observed to explore the dynamic of Cy3 in the micelles. The results showed that the Cy3 loaded micelles were stable in aqueous solution as the energy-transfer efficiency (ETE, I660/I565) rarely decreased even when the time was as long as 120 h. The ETE increased with the content of encapsulated Cy3. The FRET spectra showed that the ETE of the Cy3 loaded polymeric micelles lowered with the release of Cy3 in PBS. The intracellular tracking of the Cy3 loaded micelles found more than 60% loaded drug was release within 12 h with the calculation of ETE in FRET spectra and it was same to confocal laser scanning and flow cytometry results.

The effect of α-cyclodextrin on poly(pseudo)rotaxane nanoparticles self-assembled by protoporphyrin modified poly(ethylene glycol) for anticancer drug delivery.

Poly(pseudo)rotaxane (PPR) nanoparticles was facilely prepared using poly(ethylene glycol) (PEG) modified with protoporphyrin (PpIX) and α-cyclodextrin (α-CD) via host-guest interaction, the effect of α-CD number on the nanoparticle properties was investigated. The PEG with protoporphyrin (PEG-PpIX) end capping was synthesized via coupling reaction and the poly(pseudo)rotaxane nanoparticles with different amount of α-CD were fabricated by host-guest interaction between mPEG-PpIX and α-CDs. The final product was characterized by nuclear magnetic spectrum (1H NMR), X-ray diffraction (XRD), atomic force microscope (AFM) and dynamic light scattering (DLS). The results showed that the poly(pseudo)rotaxane nanoparticles with uniform spherical shape was successfully prepared and doxorubicin (DOX) could be efficiently encapsulated in the nanoparticles. The amount of α-CDs in poly(pseudo)rotaxane nanoparticles was proportional to micellar size and drug release rate. The nanoparticles with higher α-CD number showed better anticancer efficacy in half maximal inhibitory concentration (IC50) test. The cell internalization efficiency of DOX-loaded poly(pseudo)rotaxane nanoparticles could be further improved by lowering the α-CD number to receive smaller nanoparticle size.

Near infrared light responsive hybrid nanoparticles for synergistic therapy.

A near infrared (NIR) light responsive chromophore 7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one (DEACM) was synthesized and incorporated to ß-cyclodextrins with cRGD functionalized poly(ethylene glycol), the amphiphiles were coordinated with Au nanorods or nanoparticles to load anticancer drug doxorubicin (DOX) for fabricating hybrid nanoparticles. The π-π stacking interaction between DEACM and DOX was formed in the hybrid nanoparticles, which contributed to the high drug loading content. The Au nanorods or nanoparticles enhanced the photosolvolysis of DEACM under the irradiation of NIR with 808 nm wavelength and triggered the accelerated drug release from the nanoparticles. The drug loaded hybrid nanoparticles with NIR irradiation exhibited efficient inhibition effect on the proliferation of 4T1 breast cancer cells in vitro. The in vivo anticancer activity study on breast cancer bearing mice revealed that the hybrid nanoparticles containing Au nanorods exhibited excellent anticancer activity under the irradiation of 808 nm wavelength NIR with 800 mW.

Terminal modification of polymeric micelles with π-conjugated moieties for efficient anticancer drug delivery.

High drug loading content is the critical factor to polymeric micelles for efficient chemotherapy. Small molecules of cinnamic acid, 7-carboxymethoxy coumarin and chrysin with different π-conjugated moieties were immobilized on the terminal hydroxyl groups of PCL segments in mPEG-PCL micelles to improve drug loading content via the evocation of π-π stacking interaction between doxorubicin (DOX) and polymeric micelles. The modification of π-conjugated moieties enhanced the capability of crystallization of mPEG-PCL block copolymers. The drug loading content increased dramatically from 12.9% to 25.5% after modification. All the three modified mPEG-PCL micelles were nontoxic to cells. Chrysin modified polymeric micelles exhibited the most efficient anticancer activity. The in vivo anticancer activity of 10 mg/kg DOX dose of chrysin modified micelle formulation for twice injections was comparable to that of 5 mg/kg dose of free DOX·HCl for four injections under the circumstance of same total DOX amount. The systemic toxicity of DOX loaded chrysin modified micelles was significantly reduced. This research provided a facile strategy to achieve polymeric micelles with high drug loading content and efficient anticancer activity both in vitro and in vivo.