Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

Preparation and characterisation of the colistin-entrapped liposome driven by electrostatic interaction for intravenous administration.

Potential use of liposome for polycationic colistin is hindered by their phospholipid membrane permeability. In this study, liposomes were modified with sodium cholesteryl sulphate (Chol-SO4(-)) for improving the colistin loading by enhancing the colistin-bilayer electrostatic attraction. We have evaluated two liposomes: colistin-entrapped liposome of Chol-SO4(-) (CCL) and coated Chol-SO4(-)/colistin complex liposome (CCCL). In comparison with CCL which formed large aggregates at Chol-SO4(-)/colistin charge ratio below 2:1, CCCL showed a smaller size less dependent on the charge ratio, probably arising from more colistin entrapped on the inner leaflet of bilayer. Both liposomes exhibited significantly increased entrapment efficiency as compared with the liposome without Chol-SO4(-). But colistin released upon dilution, implying free transfer of colistin through bilayers. Pharmacokinetics results showed the approximately four-fold increase in the plasma AUC0-8 h for CCCL and CCL as compared with colistin solution, showing potential benefit for infectious target localisation by prolonging the systemic circulation of colistin.

Photothermal controlled-release microcapsule pesticide delivery systems constructed with sodium lignosulfonate and transition metal ions: construction, efficacy and on-demand pesticide delivery.

BACKGROUND: Widespread application of controlled-release pesticide delivery systems is a feasible and effective method to improve the utilization efficiency of pesticides. However, owing to the high cost and complicated preparation technologies of controlled-release pesticide delivery systems, their applications in agricultural production have been seriously hindered. RESULTS: This study aimed to construct inexpensive photothermally controlled-release pesticide delivery systems using chitosan (CS) and sodium lignosulfonate (LS) as the wall materials, and a coordination assembly strategy of LS with transition metal ions to encapsulate a model pesticide, avermectin (AVM). The resulting complex or nanoparticle photothermal layers in these systems effectively achieved photothermal conversions, and replaced the use of common photothermal agents. In the prepared pesticide-delivery systems, two systems had remarkable photothermal conversion performance and photothermal stabilities with a photothermal conversion efficiency (η) of 24.03% and 28.82%, respectively, under 808 nm, 2 W near-infrared irradiation. The slow-release and ultraviolet-shielding performance of these two systems were markedly enhanced compared with other formulations. The insecticidal activities of these two systems against Plutella xylostella under irradiation with light-emitting diode (LED)-simulated sunlight were also enhanced by 5.20- and 5.06-fold, respectively, compared with that without irradiation of LED-simulated sunlight. CONCLUSION: Because of their convenient preparations, inexpensive and renewable raw materials, and excellent photothermally controlled-release performance, these on-demand pesticide delivery systems might have significant potential in improving the utilization efficiency of pesticides in modern agriculture. © 2024 Society of Chemical Industry.

Balancing the stability and drug activation in adaptive nanoparticles potentiates chemotherapy in multidrug-resistant cancer.

Rationale: Prodrug strategies that render the drug temporarily inactive through a cleavable linkage are able to modulate the physicochemical properties of drugs for adaptive nanoparticle (NP) formulation. Here we used cabazitaxel as a model compound to test the validity of our "balancing NP stability and specific drug activation" strategy. Methods: Cabazitaxel is conjugated to hydrophobic polylactide fragments with varying chain lengths via a self-immolation linkage, yielding polymeric prodrugs that can be reactivated by reductive agents in cells. Following a nanoprecipitation protocol, cabazitaxel prodrugs can be stably entrapped in amphiphilic polyethylene-block-polylactide matrices to form core-shell nanotherapies with augmented colloidal stability. Results: Upon cellular uptake followed by intracellular reduction, the NPs spontaneously release chemically unmodified cabazitaxel and exert high cytotoxicity. Studies with near-infrared dye-labeled NPs demonstrate that the nanodelivery of the prodrugs extends their systemic circulation, accompanied with increased drug concentrations at target tumor sites. In preclinical mouse xenograft models, including two paclitaxel-resistant xenograft models, the nanotherapy shows a remarkably higher efficacy in tumor suppression and an improved safety profile than free cabazitaxel. Conclusion: Collectively, our approach enables more effective and less toxic delivery of the cabazitaxel drug, which could be a new generalizable strategy for re-engineering other toxic and water-insoluble therapeutics.

Facile surface functional polyetheretherketone with antibacterial and immunoregulatory activities for enhanced regeneration toward bacterium-infected bone destruction.

Existing biologically inert or unmodified implants to treat infectious bone defects or osteomyelitis still cannot effectively solve bacterial infection and osseointegration. In this work, a simple co-deposition strategy was developed to modify porous polyetheretherketone (PEEK) with improved antibacterial activity and controllable immunoregulatory ability. After PEEK was treated by H2SO4 to obtain porous PEEK (SPEEK), the self-polymerization of dopamine was operated on SPEEK in the solution of dopamine and gentamicin sulfate (GS) to prepare polydopamine (pDA) and GS layer-modified SPEEK (labeled as SPEEK-pDA-GS). The morphology, surface property, and molecular structure of SPEEK-pDA-GS were investigated. Besides the antibacterial property of SPEEK-pDA-GS ascribed to the successful immobilization of GS, SPEEK-pDA-GS exhibited promoted osseointegration through the results of mineralization, alkaline phosphatase (ALP) levels and osteogenic gene expression. Furthermore, the evaluation of the cell proliferation suggested that SPEEK-pDA-GS possessed the biocompatibility and the immunoregulatory ability that induced macrophages to anti-inflammatory M2 phenotype. Using rat as model, in vivo results containing X-ray, µ-CT, immunohistochemistry, and pathological analysis showed the excellent healing effect of SPEEK-pDA-GS on bone defect with infection with biological safety. This work illustrates a new insight into the simple and effective modification of PEEK and other implants with antibacterial, immunoregulatory, and osseointegration abilities for clinical requirement.

Transforming a toxic drug into an efficacious nanomedicine using a lipoprodrug strategy for the treatment of patient-derived melanoma xenografts.

Despite the progress made with the recent clinical use of the anticancer compound cabazitaxel, the efficacy in patients remains unsatisfactory, largely due to the high in vivo toxicity of the agent. Therefore, strategies that achieve favorable outcomes and good safety profiles will greatly expand the repertoire of this potent agent. Here, we propose a combinatorial strategy to reform the cabazitaxel agent and the use of sequential supramolecular nanoassembly with liposomal compositions to assemble a prodrug-formulated liposome, termed lipoprodrug, for safe and effective drug delivery. Reconstructing cabazitaxel with a polyunsaturated fatty acid (i.e., docosahexaenoic acid) via a hydrolyzable ester bond confers the generated prodrug with the ability to be readily integrated into the lipid bilayer of liposomes for systemic administration. The resulting lipoprodrug scaffold showed significantly sustained drug release profiles and improved pharmacokinetics in rats as well as a reduction in systemic toxicity in vivo. Notably, the lipoprodrug outperformed free cabazitaxel in terms of in vivo therapeutic efficacy in multiple separate tumor xenograft-bearing mouse models, one of which was a patient-derived xenograft model. Surprisingly, the lipoprodrug was able to reduce tumor invasiveness and reprogram the tumor immunosuppressive microenvironment by proinflammatory macrophage polarization. Our findings validate this lipoprodrug approach as a simple yet effective strategy for transforming the highly toxic cabazitaxel agent into an efficacious nanomedicine with excellent in vivo tolerability. This approach could also be applied to rescue other drugs or drug candidates that have failed in clinical trials due to poor pharmacokinetic properties or unacceptable toxicity in patients.

Preparation and characterization of the ion-fixed mixed micelles with superior stability.

The inherent instability of micelles remains a main challenge for antitumor drug delivery, the objective of this study is to prepare and characterize the ion-fixed mixed micelles with significantly improved stability. The mixed micelles and ion-fixed mixed micelles combining the carboxy-containing PLA (PLA-COO(-)) and mPEG-PLA were formed by inserting PLA-COO(-) into micellar core without and with metal ions, respectively. The critical micelle concentration (CMC) of mixed micelle depended on the origin PLA length in the mPEG-PLA, whereas kinetic stability of the mixed micelles was significantly improved, irrespective of the PLA length. However, curcumin (Cur)-loaded mixed micelles did not show higher physical stability upon dilution and Cur-micelle bonding constant due to the lower loading space. On the contrary, the ion-fixed mixed micelles formed in the presence of CaCl2 solution showed a high physical stability upon dilution due to the solidification of micellar core by forming the more hydrophobic (PLA-COO(-))2 Ca(2+) complex. The Cur-loaded ion-fixed mixed micelles showed the comparable cellular uptake of Cur and cytotoxicity in comparison with mPEG-PLA micelles. Our study highlights a universal combining strategy of ion-fixed mixed micelles with superior stability to individual micelles for antitumor drug delivery.