One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.

Bioactive ceramics have received great attention in the past decades owing to their success in stimulating cell proliferation, differentiation and bone tissue regeneration. They can react and form chemical bonds with cells and tissues in human body. This paper provides a comprehensive review of the application of bioactive ceramics for bone repair and regeneration. The review systematically summarizes the types and characters of bioactive ceramics, the fabrication methods for nanostructure and hierarchically porous structure, typical toughness methods for ceramic scaffold and corresponding mechanisms such as fiber toughness, whisker toughness and particle toughness. Moreover, greater insights into the mechanisms of interaction between ceramics and cells are provided, as well as the development of ceramic-based composite materials. The development and challenges of bioactive ceramics are also discussed from the perspective of bone repair and regeneration.

Research into long-circulating nanoparticles has in the past focused on reducing their clearance by macrophages. By engineering a hierarchical polyethylene glycol (PEG) structure on nanoparticle surfaces, we revealed an alternative mechanism to enhance nanoparticle blood circulation. The conjugation of a second PEG layer at a density close to but lower than the mushroom-to-brush transition regime on conventional PEGylated nanoparticles dramatically prolongs their blood circulation via reduced nanoparticle uptake by non-Kupffer cells in the liver, especially liver sinusoidal endothelial cells. Our study also disclosed that the dynamic outer PEG layer reduces protein binding affinity to nanoparticles, although not the total number of adsorbed proteins. These effects of the outer PEG layer diminish in the higher density regime. Therefore, our results suggest that the dynamic topographical structure of nanoparticles is an important factor in governing their fate in vivo. Taken together, this study advances our understanding of nanoparticle blood circulation and provides a facile approach for generating long circulating nanoparticles.

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A well-defined pyrrolidone based thermoresponsive polymer, poly [N-(2-methacryloyloxyethyl) pyrrolidone] (PNMP), was synthesized via reversible addition-fragmentation chain transfer radical polymerization or RAFT polymerization of N-(2-methacryloyloxyethyl) pyrrolidone monomer in methanol under a mild Visible light radiation at 30 °C. The average molecular weights and polydispersity indices of PNMP polymers were characterized by gel permeation chromatography (GPC) and static light scattering analysis. The kinetic studies indicated that this RAFT polymerization exhibited a well-controlled behavior. The living character of this RAFT polymerization was confirmed by the facile synthesis of a series of well-defined PNMP-based block copolymers via RAFT polymerization under this mild visible light radiation at 30 °C using the above-synthesized PNMP polymer as a macromolecular chain transfer agent. Temperature-variation 1 H NMR unambiguously revealed that the PNMP polymer with weight-average molecular weight (M w ) of 105.4 kg mol -1 and polydispersity index (M w /M n ) of 1.11 was molecularly dissolved in D 2 O at ambient temperature, e.g. 22 °C. Upon elevating the solution temperature, the dehydration process of this fully hydrated PNMP polymer was triggered at 46.1 °C, leading to a dramatic decrease of integral ratios of proton resonance signals of PNMP to that of D 2 O. Further elevating the solution temperature to 51.9 °C led to a sharp phase separation of PNMP polymer from aqueous solution. Laser light scattering analyses demonstrated that the cloud point of the PNMP polymer decreased with molecular weight in the M w range of 20.6-105.4 kg mol -1 . Moreover, this PNMP polymer exhibited a remarkably reversible thermoresponsive dehydration/hydration and phase transition behaviors in aqueous solution. Unlike what was observed in PNIPAM aqueous solution, no hysteresis phenomenon was observed in PNMP aqueous solution during one heating-and-cooling cycle.

Background: Cancer is one of the major causes of death and is difficult to cure using existing clinical therapies. Clinical cancer treatments [such as surgery, chemotherapy (CHT), radiotherapy (RT) and immunotherapy (IT)] are widely used but they have limited therapeutic effects and unavoidable side effects. Recently, the development of novel nanomaterials offers a platform for combinational therapy (meaning a combination of two or more therapeutic agents) which is a promising approach for cancer therapy. Recent studies have demonstrated several types of nanomaterials suitable for photothermal therapy (PTT) based on a near-infrared (NIR) light-responsive system. PTT possesses favorable properties such as being low in cost, and having high temporospatial control with minimal invasiveness. However, short NIR light penetration depth limits its functions. Methods: In this review, due to their promise, we focus on inorganic nanomaterials [such as hollow mesoporous silica nanoparticles (HMSNs), tungsten sulfide quantum dots (WS 2 QDs), and gold nanorods (AuNRs)] combining PTT with CHT, RT or IT in one treatment, aiming to provide a comprehensive understanding of PTT-based combinational cancer therapy. Results: This review found much evidence for the use of inorganic nanoparticles for PTTbased combinational cancer therapy. Conclusion: Under synergistic effects, inorganic nanomaterial-based combinational treatments exhibit enhanced therapeutic effects compared to PTT, CHT, RT, IT or PDT alone and should be further investigated in the cancer field.

This paper describes the molecular structure dependent thermoresponsive behaviors of pyrrolidone-based water-soluble polymers. A series of well-defined poly[N-(2-methacryloyloxyethyl)pyrrolidone] (PNMEP), poly[N-(3-acryloyloxypropyl)pyrrolidone] (PNAPP), and poly[N-(3-methacryloyloxypropyl)pyrrolidone] (PNMPP) were synthesized via visible light activating RAFT polymerization at 25 °C. Kinetic studies indicate a rapid and well-controlled behavior of this polymerization. Gel permeation chromatography (GPC) and 1H NMR analysis confirm their intact molecular structure, well-defined molecular weight, and narrow distribution. Laser light scattering and temperature-variable 1H NMR analyses demonstrate that the cloud point of a PNMEP sample at a degree of polymerization (DP) of 96 is 1.5 °C lower than that of PNAPP at a DP = 104. Additional backbone methyl groups in PNMPP lead to a dramatic cloud point lowering, e.g., cloud point of PNMPP at a DP = 100 is 37 °C lower than that of PNAPP at a DP = 104. This is contrary to what was observed in poly(N-isopropylacrylamide) (PNIPA) and its polymethacrylamide analogues. These pyrrolidone-based polymers show a dramatic solvent isotopic effect that is different from that of PNIPA; e.g., the cloud point of PNMEP at a DP = 237 is 8.5 °C lower in D2O than in H2O. Increasing polymer chain length or hydrophobicity may suppress this solvent isotopic effect. This phase transition is correlated to Hofmeister series but more sensitive than PNIPA. Na2CO3 dramatically lowers cloud point, while NaI significantly improves cloud point, up to full dissolution in H2O at 95 °C. The solvent isotopic effect in NaCl or Na2CO3 solution is the same as what observed in solution absent of salt. Upon heating D2O solution of PNMEP, the polymer first forms the hydrated irregular colloidal aggregates near the cloud point, the phase transition occurs at the fully hydrated state at cloud point, and further heating leads to the dehydration and separation from D2O. However, in NaCl solution, the dehydration of PNMEP occurs subsequently from apolar backbones, spacers, and finally pyrrolidone groups.

Well-defined polystyrene and its functional derivatives, poly(vinylbenzyl chloride) (PVBC), poly-(N,N-diethyl vinylbenzylamine) (PDEVBA), and poly(vinylbenzyl alcohol) (PVBA) were synthesized via (S)-1-dodecyl-(S′)-(R,R′-dimethyl-R′′-acetic acid) trithiocarbonate-mediated ambient-temperature reversible additionfragmentation chain transfer radical (RAFT) polymerization of the corresponding styrenic-based monomers under mild long-waVe radiation, using a (2,4,6-trimethylbenzoyl) diphenylphosphine oxide photoinitiator. The effect of chloromethyl, hydroxymethyl, and tert-amino functionalities on reactivity and controlled behavior of ambienttemperature RAFT polymerization of styrenic-based monomers under mild conditions was studied in this paper. The results indicated that the photolysis of trithiocarbonate groups and the irreversible termination reactions of their intermediate radicals were significantly suppressed for the duration of the RAFT polymerization under mild long-wave radiation, thus keeping the characteristic living behavior. Kinetic studies confirmed the well-controlled behavior of these RAFT polymerizations. Moreover, the chloromethyl, tert-amino, or hydroxymethyl functionalities significantly improved reactivity of styrenic-based monomers, thus remarkably accelerating the process of ambienttemperature RAFT polymerization. Although RAFT polymerization of DEVBA and VBC monomers proceeded at a comparable rate, the initialization period in RAFT polymerization of DEVBA monomer was clearly longer than that of the VBC monomer. VBA was the most reactive monomer among these styrenic-based monomers. Ambient-temperature RAFT polymerization of VBA under mild long-wave radiation was well controlled up to 31% monomer conversion in 1.5 h. The living behavior of these ambient-temperature RAFT polymerizations facilitated the direct synthesis of well-defined all-styrenic-based block copolymers under mild conditions.