A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.

Maternal procymidone exposure has lasting effects on murine gut-liver axis and glucolipid metabolism in offspring.

There is increasing evidence that maternal exposure to environmental pollutants can cause intestinal and metabolic diseases, and these disease risks still exist in offspring. Here, female C57BL/6 mice were orally treated with procymidone (PRO) (10 and 100 mg/kg body weight/day) by dietary supplementation during the gestation and lactation periods. Then, we discovered PRO changed the physiology, intestinal barrier and metabolism both in the generations of F0 and different developmental stages of F1 (7 weeks and 30 weeks old, respectively). Maternal PRO exposure affected the growth phenotypes and the glucolipid metabolism related indicators and genes of mice, especially the male mice of F1 generations. The changes in bile acids (BAs) metabolism demonstrated that PRO disordered glucolipid metabolism through enterohepatic circulation. Furthermore, PRO reduced mucus secretion in the gut and altered the composition of gut microbiota, leading more bacteria to disseminate in the gut and inflammatory responses both in F0 and F1 regenerations. And PRO-induced gut microbiota dysbiosis was tightly related to BAs metabolites. Together, the results indicated that PRO destructed the functional integrity of intestinal barrier and the inflammatory reaction was triggered. And then, the disorder of glucolipid metabolism was induced through the BAs enterohepatic circulation. This study indicated that the cross-generation effects of PRO could not be ignored.

NIR-triggered ligand-presenting nanocarriers for enhancing synergistic photothermal-chemotherapy.

Surface PEGylation of nanomedicine is effective for prolonging blood circulation time and facilitating the EPR effect, whereas the hydrophilic stealth surface inhibits effective cellular uptake and hinders active targeting. To address the dilemma, herein, a NIR light-triggered dePEGylation/ligand-presenting strategy based on thermal decomposition of azo bonds is developed, whereby Dox/Pz-IR nanoparticle is self-assembled from thermo-labile azo molecule-linked long PEG chain polymer (Pz-IR), cRGD-conjugated IR783 with short PEG chains (rP-IR) and doxorubicin. The long PEG chains could mask cRGD peptides in the blood circulation, preventing serum degradation and nonspecific interaction with normal cells. Once exposed to NIR laser, the PEG corona is stripped off owing to the rupture of azo bonds through the photothermal effect of IR783, and the masked cRGD peptides are exposed, which remarkably enhances cellular uptake by tumor cells and improves tumor accumulation. Dox/Pz-IR achieves the optimal synergy of photothermal-chemotherapy at mild temperature through progressive tumor accumulation, precisely regulated photothermal effect and NIR-PTT induced pulsated drug release. The strategy of NIR photo-driven dePEGylation/targeting offers a new approach to overcoming the "PEG dilemma", and provides a noval avenue for programmed tumor-targeted drug delivery.

Injectable in Situ Forming Hydrogels of Thermosensitive Polypyrrole Nanoplatforms for Precisely Synergistic Photothermo-Chemotherapy.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol-gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π-π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy-chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.

Precise synchronization of hyperthermia-chemotherapy: photothermally induced on-demand release from injectable hydrogels of gold nanocages.

Though a therapeutic sequence plays a key role in tumor therapy, little attention has been paid to its influence on multimodal combined therapy. Herein, we developed gold nanocages (GNC@PNA-hls) decorated with two kinds of temperature sensitive p(N-isopropyl-acrylamide-acrylic acid) copolymers (PNA-hs and PNA-ls) for precise antitumor coordination of thermo-chemotherapy. Doxorubicin-loaded GNC@PNA-hls (Dox-GNC@PNA-hls) showed a steady photothermally induced on-demand release under multiple near-infrared (NIR) irradiations. In vitro evaluations indicated that concurrent thermo-chemotherapy treatments (Dox - L) showed the best antitumor effect, compared with the sequence of either doxorubicin treatment followed by NIR radiation (Dox + L) or NIR radiation followed by doxorubicin treatment (L + Dox). The in vivo antitumor efficacy also indicated that the tumor volume was totally suppressed (ca. 0.14 cm3) by the treatment of Dox-GNC@PNA-hls with NIR radiation for 14 days. These results indicated that Dox-GNC@PNA-hls could achieve precise synchronization between hyperthermia and chemotherapy, and effectively enhance their antitumor efficacy.

Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization.

Transcatheter arterial embolization (TAE) plays an important role in clinical tumor therapy by accomplishing vessel-casting embolization of tumor arteries at all levels and suppressing tumor collateral circulation and vascular re-canalization. In this study, we describe smart blood-vessel-embolic nanogels for improving the anti-tumor efficacy of TAE therapy on hepatocellular carcinoma (HCC). Methods: In this study, an in vitro model composed of two microfluidic chips was used for simulating the tumor capillary network and analyzing artery-embolization properties. Also, blood-vessel-casting embolization of renal arteries was evaluated in normal rabbits. Using a VX2 tumor-bearing rabbit model, the therapeutic efficacy of TAE on HCC was investigated for tumor growth, necrosis, and proliferation. Neovascularization and collateral circulation were evaluated by immunofluorescent detection of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and CD31 following the TAE therapy of VX2 tumor-bearing rabbits. Results: Sufficient embolization of all eight levels of micro-channels was achieved in a tumor-vessel-mimetic model with two microfluidic chips using PIBI-2240, and was further confirmed in renal arteries of normal rabbit. Effective inhibition of tumor collateral circulation and vascular re-canalization was observed in VX2 tumor-bearing rabbits due to the reduced expression levels of HIF-1α, VEGF, and CD31. Conclusions: The exceptional anti-tumor effect of PIBI-2240 observed in this study suggested that it is an excellent blood-vessel-embolic material for tumor TAE therapy.

Cisplatin-directed coordination-crosslinking nanogels with thermo/pH-sensitive triblock polymers: improvement on chemotherapic efficacy via sustained release and drug retention.

To realize the sustained release and long-term intratumoural retention of water-soluble cisplatin, thermo/pH-sensitive cisplatin-directed coordination-crosslinking nanogels (Pt-PNA) were developed via the coordination bonds of Pt-carboxyl groups. As the coordination ratio (CR) of the Pt-carboxyl bonds increased from 5% to 35%, the sizes of the Pt-PNA nanogels decreased from 999 nm to 167 nm, and their zeta potentials increased from -35 mV to -13 mV. Only through a simple mixing of cisplatin and PNAs, the entrapment efficiencies (EEs) of the Pt-PNA nanogels reached near 100% (>90%), and the drug-loading amounts (DLs) of cisplatin could achieve up to 25.5 ± 0.1%. For water-soluble cisplatin, Pt-PNA nanogels exhibited a sustained release for as long as 5 days. The thermo/pH-sensitive sol-gel phase-transition behaviour of the Pt-PNA nanogels were investigated via inverting-vial and rheological methods. Platinum elemental analysis indicated that the Pt-PNA nanogels showed a much stronger ability of cisplatin retention in tumours than free cisplatin. The platinum content in a tumour treated by the Pt-PNA nanogels was far higher than that by free cisplatin: 200.7 ± 63.6 µg vs. 82.7 ± 26.8 µg at the 1st day, or 118.9 ± 35.2 µg vs. 18.5 ± 9.4 µg at the 14th day. The evaluation of the in vivo antitumour efficacy indicated that only after a single dose of Pt-PNA nanogels, the tumour volume continuously decreased to 0.73 ± 0.07 times that of the original tumour volume (OTV) for 14 days; however, it rapidly increased by 3.37 ± 0.82, 8.01 ± 0.53 and 9.25 ± 1.85 times that of the OTV with the same dose of free cisplatin, PNA, and NS, respectively. Some preliminary evaluations of the biocompatibility indicated that the toxic side effects of cisplatin could be greatly improved via cisplatin-directed coordination-crosslinking with PNA. As a result, Pt-PNA nanogels could likely become a promising versatile strategy for improving antitumour efficacy and reducing the toxicity and size effects of platinum-based drugs, and they could also be developed as promising nanomedicines for regional chemotherapy.

Nanogel-based scaffolds fabricated for bone regeneration with mesoporous bioactive glass and strontium: In vitro and in vivo characterization.

The delivery of novel bioactive scaffolds for the repair of bone defects remains a prominent challenge worldwide. Currently osteoporosis, a disease caused by low bone mineral density affects over 200 million people worldwide with up to half of this population experiencing at least one fracture within their lifetime. Recently temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogel (PIB nanogel) scaffolds have emerged as biomaterial candidate for regenerative therapies. It has the advantage of being injected from syringes as a soluble gel form (capable of delivering growth and/or living progenitor cells) yet hardens once it reaches body temperatures. Although this material demonstrates optimal clinical delivery of scaffolds, its main drawback is its low osteoconductivity and bioactivity. Recently we have demonstrated that mesoporous bioactive glass (MBG) loaded with strontium was able to regenerate osteoporotic defects in vivo and enhance osteoblast differentiation in vitro. The aim of this study was to combine the advantages of these two therapies and prepare PIB-nanogel scaffolds containing Sr-MBG and investigate their ability to regenerate femur defects created in ovarectamized rats. The results demonstrate that groups containing Sr-MBG within the nanogel formulation had significantly higher new bone formation when compared with other modalities. We further demonstrate that although nanogel demonstrated poor osteogenic ability, the addition of osteoblasts worked synergistically with Sr-MBG particles to enhance the regeneration of the created femur defects in osteoporotic animals. In conclusion, PIB nanogel scaffolds are a viable treatment modality for bone tissue engineering and may serve as a carrier-scaffold for osteogenic cells and/or bioactive scaffolds such as Sr-MBG. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1175-1183, 2017.

Doxorubicin-induced co-assembling nanomedicines with temperature-sensitive acidic polymer and their in-situ-forming hydrogels for intratumoral administration.

Doxorubicin (DOX)-induced co-assembling nanomedicines (D-PNAx) with temperature-sensitive PNAx triblock polymers have been developed for regional chemotherapy against liver cancer via intratumoral administration in the present work. Owing to the formation of insoluble DOX carboxylate, D-PNAx nanomedicines showed high drug-loading and entrapment efficacy via a simple mixing of doxorubicin hydrochloride and PNAx polymers. The sustained releasing profile of D-PNA100 nanomedicines indicated that only 9.4% of DOX was released within 1day, and 60% was released during 10days. Based on DOX-induced co-assembling behavior and their temperature sensitive in-situ-forming hydrogels, D-PNA100 nanomedicines showed excellent antitumor activity against H22 tumor using intratumoral administration. In contrast to that by free DOX solution (1.13±0.04 times at 9days) and blank PNA100 (2.11±0.34 times), the tumor volume treated by D-PNA100 had been falling to only 0.77±0.13 times of original tumor volume throughout the experimental period. In vivo biodistribution of DOX indicated that D-PNA100 nanomedicines exhibited much stronger DOX retention in tumor tissues than free DOX solution via intratumoral injection. D-PNA100 nanomedicines were hopeful to be developed as new temperature sensitive in-situ-forming hydrogels via i.t. injection for regional chemotherapy.

The stimuli-responsive multiphase behavior of core-shell nanogels with opposite charges and their potential application in in situ gelling system.

Concentrated p(N-isopropylacrylamide) (PNIPAM) nanogel dispersions exhibited rich temperature-sensitive sol-gel phase transition behavior. In the present work, the influence of electrostatic forces between nanogel particles, including attraction and repulsion, on the sol-gel phase transition behavior of PNIPAM nanogel dispersions has been studied. Both oppositely charged nanogels with core-shell structures (NIA and PND nanogels) were synthesized, and their shell charges were calculated to -0.33 and 0.082 mmol/g by potentiometric titration method. When mixed with various ratio of negative and positive charge (NC value), the resultant mixture dispersions of NIA and PND nanogel (OCNs) exhibited different aggregating behavior from NIA and PND nanogels. OCN-e aggregates (NC value=1/4), which exhibited temperature-independence of electric neutrality, had the maximum size, about 1.9-2.2 times larger than NIA or PND nanogels. Concentrated OCN-e dispersions exhibited stronger ability to form shrunken gel. Its CGC was about 2.0 wt%, 4-times lower than that of NIA and PND nanogels (about 8.0 wt%). In vitro and in vivo gelling results indicated that OCN-e aggregates could form free-standing gel with good mechanical strength, and were promising to be developed as new in situ gelling system.

The studies about doxorubicin-loaded p(N-isopropyl-acrylamide-co-butyl methylacrylate) temperature-sensitive nanogel dispersions on the application in TACE therapies for rabbit VX2 liver tumor.

Transarterial chemo-embolization (TACE), which combined embolization therapy and chemotherapy, has become the most widely used treatment for unresectable liver cancer. Blood-vessel-embolic materials play key role on TACE. In the present work, doxorubicin-loaded p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels-iohexol dispersions (IBi-D) were reported firstly for TACE therapy to liver cancer. Using inverting-vial method, IBi-D dispersions showed three phases (swollen gel, flowable sol and shrunken gel) as temperature increased. Although Dox had little effect on the CGTs between flowable and shrunken gel, the rheological properties of IBi-D dispersions could greatly improved by Dox. A sustained Dox-release, which was necessary in TACE therapy, was found from IBi-D dispersions in the eluting medium of PBS buffers. The studies about renal artery embolization of normal rabbits indicated that IBi-D dispersions showed good properties in embolizing all kinds of renal arteries (including peripheral, small and large arteries) by controlling their injecting dosages. Angiography and medical evaluation indicated that TACE therapy of IBi-D dispersions has better efficacy on rabbit VX2 liver tumors than TAC treatment of free Dox and TAE treatment of IBi dispersions.

In vivo experimental study on bone regeneration in critical bone defects using PIB nanogels/boron-containing mesoporous bioactive glass composite scaffold.

PURPOSE: In the present study, the fabrication of novel p(N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogels was combined with boron-containing mesoporous bioactive glass (B-MBG) scaffolds in order to improve the mechanical properties of PIB nanogels alone. Scaffolds were tested for mechanical strength and the ability to promote new bone formation in vivo. PATIENTS AND METHODS: To evaluate the potential of each scaffold in bone regeneration, ovariectomized rats were chosen as a study model to determine the ability of PIB nanogels to stimulate bone formation in a complicated anatomical bone defect. PIB nanogels and PIB nanogels/B-MBG composites were respectively implanted into ovariectomized rats with critical-sized femur defects following treatment periods of 2, 4, and 8 weeks post-implantation. RESULTS: Results from the present study demonstrate that PIB nanogels/B-MBG composites showed greater improvement in mechanical strength when compared to PIB nanogels alone. In vivo, hematoxylin and eosin staining revealed significantly more newly formed bone in defects containing PIB nanogels/B-MBG composite scaffolds when compared to PIB nanogels alone. Tartrate-resistant acid phosphatase-positive staining demonstrated that both scaffolds were degraded over time and bone remodeling occurred in the surrounding bone defect as early as 4 weeks post-implantation. CONCLUSION: The results from the present study indicate that PIB nanogels are a potential bone tissue engineering biomaterial able to treat defects of irregular shapes and deformities as an injectable, thermoresponsive, biocompatible hydrogel which undergoes rapid thermal gelation once body temperature is reached. Furthermore, its combination with B-MBG scaffolds improves the mechanical properties and ability to promote new bone formation when compared to PIB nanogels alone.

The studies on highly concentrated complex dispersions of gold nanoparticles and temperature-sensitive nanogels and their application as new blood-vessel-embolic materials with high-resolution angiography.

Recently temperature sensitive polymers have been developed as novel embolization materials. However, their flowability and embolization have been seriously impacted by iodine-based X-ray contrast agents. In order to resolve the drawbacks of these contrast agents, highly concentrated complex (HCC) dispersions of gold nanoparticles (GNPs) with p(N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogels were developed as new blood-vessel-embolic materials with high-resolution angiography. Although GNPs have better X-ray attenuation than iodinated compounds, their poor dispersion stability limits their application in digital subtraction angiography (DSA). HCC dispersions show excellent X-ray attenuation ability which is 2.6 times higher than Omnipaque at 0.31 mol L-1. This can be attributed to the fact that the sol-gel transition of nanogel dispersions improves the colloid stability of GNPs. In the two sol-gel transition temperatures (Tg-s and T's-g) of nanogel dispersions, GNPs have no influence on T's-g, and a great influence on Tg-s. The in vivo experimental data indicate that HCC dispersions show high angiographic ability and good blood-vessel embolization, and can be used for postoperative examination for long periods owing to the entrapment of GNPs into the embolic sites. The HCC dispersions have potential to be developed as new blood-vessel-embolic materials with high-resolution angiography.