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[Display omitted] Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO 2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H 2 O 2 into O 2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O 2 -enhanced efficient topical dual-phototherapy of breast cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO 2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H 2 O 2 into O 2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O 2 -enhanced efficient topical dual-phototherapy of breast cancer. [ABSTRACT FROM AUTHOR]

Highlights • HA hydrogel was prepared via hydrazone-/photo- dual crosslinking process. • HA hydrogel had topography and mechanical property similar to breast tumor tissue. • HA hydrogel promoted MCF-7 cells to cluster and secrete VEGF, bFGF and IL-8. • 3D culture enhanced cell migration and invasion potentials and in vivo tumorigenesis. Abstract In tumor biology, it is widely recognized that 3D rather than 2D cell culture can recapitulate key features of solid tumors, including cell-extracellular matrix (ECM) interactions. In this study, to mimick the ECM of breast cancer, hyaluronic acid (HA) hydrogels were synthesized from two polyvalent HA derivatives through a hydrazone and photo dual crosslinking process. HA hydrogels could be formed within 120 s. The hydrogels had similar topography and mechanical properties to breast tumor and displayed glutathione and hyaluronidase dual-responsive degradation behavior. Biological studies demonstrated that HA hydrogel could support the proliferation and clustering of breast cancer MCF-7 cells. The expression levels of VEGF, IL-8 and bFGF in hydrogel-cultured cells were significantly greater than those in 2D culture. Moreover, cells from hydrogel culture exhibited greater migration/invasion abilities and tumorigenicity than 2D-cultured cells. Therefore, the HA hydrogels are a promising ECM-mimicking matrix for in vitro construction of breast cancer. [ABSTRACT FROM AUTHOR]

2D cell culture is widely utilized to develop anti-cancer drugs and to explore the mechanisms of cancer tumorigenesis and development. However, the findings obtained from 2D culture often fail to provide guidance for clinical tumor treatments since it cannot precisely replicate the features of real tumors. 3D tumor models capable of recapitulating native tumor microenvironments have been proved to be a promising alternative technique. Herein, we constructed a breast tumor model from novel hyaluronic acid (HA) hydrogel which was prepared through photocrosslinking of methacrylated HA. The hydrogel was used as a biomimetic extracellular matrix to incubate MCF-7 cells. It was found that methacrylation degree had great effects on hydrogel's microstructure, mechanical performances, and liquid-absorbing and degradation abilities. Optimized hydrogel exhibited highly porous morphology, high equilibrium swelling ratio, suitable mechanical properties, and hyaluronidase-responsive degradation behavior. The results demonstrated that the HA hydrogel facilitated MCF-7 cell proliferation and growth in an aggregation manner. Furthermore, 3D-cultured MCF-7 cells not only up-regulated the expression of VEGF, bFGF and interleukin-8 but exhibited greater invasion and tumorigenesis capabilities compared with 2D-cultured cells. Therefore, the HA hydrogel is a reliable substitute for tumor model construction. [Display omitted] • The hyaluronic acid hydrogel was synthesized by a facile photo-crosslinking approach. • 3D breast tumor models were successfully constructed from hyaluronic acid hydrogels. • 3D-cultured MCF-7 cells efficiently replicated key cellular features of tumor in vivo. • 3D-cultured MCF-7 cells exhibited enhanced tumorigenicity than 2D-cultured ones. [ABSTRACT FROM AUTHOR]

Combination of different therapy modalities with multiple tumoricidal mechanisms has emerged as a promising anticancer strategy. Herein, we reported an aldehyde/catechol-functionalized hyaluronic acid (DAHA) and hydroxyethyl chitosan (HECS) decorated gold nanorod (GNR) platform for combined chemo-photothermal therapy of breast cancer. The DAHA was synthesized by conjugating dopamine onto oxidized hyaluronic acid. The nanoplatform was prepared by successively modifying GNR with DAHA via Au-catechol bonds, conjugating DOX onto DAHA moiety through Schiff base linkage, and coating HECS interlayer for charge-reversal and hyaluronic acid corona for tumor cell targeting. The resulting nanoplatform GNR-HADOXCH exhibited acid-triggered surface charge-reversal and pH/NIR dual-responsive drug release behaviors. The nanoplatform could be efficiently internalized into MCF-7 breast cancer cells and displayed greater cancer cell killing than individual modalities. Therefore, polysaccharide decoration could ensure the co-delivery of GNR and DOX into cancer cells, and the developed GNR-HADOXCH holds great potential for breast cancer treatment. Unlabelled Image • The versatile nanoplatform was prepared via a facile and effective self-assembly method. • The nanoplatform exhibited acid-triggered surface charge-reversal property. • The nanoplatform had pH/NIR dual-responsive drug release behavior. • Receptor recognition and charge-reversal dual-enhanced cellular internalization. • MCF-7 cells could be efficiently killed by combined chemo-photothermal therapy. [ABSTRACT FROM AUTHOR]

• Multifunctional PEG-b-polypeptide-decorated gold nanorod nanoplatform was developed. • DOX was conjugated onto the nanoplatform via pH-sensitive hydrazone linkage. • Release behavior of DOX from the nanoplatform was reduction/pH dual-responsive. • Combined photothermal chemotherapy achieved great anti-cancer efficacy in MCF-7 cells. The combination of chemotherapy and photothermal therapy is acknowledged as one of the most promising approaches in cancer treatment. Targeted delivery and controlled drug release are two important factors for combined chemo-photothermal therapy. In this study, a multifunctional nanoplatform based on gold nanorod (GNR) decorated with folate-conjugated poly(ethylene glycol)- b -poly(L-γ-glutamylhydrazine) (FEGGH) containing disulfide linker and dihydroxyphenyl groups was developed for targeted combined chemo-photothermal therapy of breast cancer. FEGGH was synthesized by ring-opening polymerization of γ-benzyl- l -glutamate -N- carboxyanhydride using folate/cystamine-heterobifunctionalized poly(ethylene glycol) as an initiator, following by hydrazinolysis and carbodiimide reactions. FEGGH was decorated onto GNR through Au-catechol bonds. Chemotherapeutic drug doxorubicin (DOX) was loaded onto the nanoplatform through pH-sensitive hydrazone linkage, obtaining final product FEGGHDOX-GNR. The DOX-loaded nanoplatform displayed excellent photostability and reduction/pH dual-responsive drug release behavior. Cytological studies demonstrated the effective internalization of FEGGHDOX-GNR into MCF-7 cells via folate-mediated endocytosis and additive therapeutic effect of combined photothermal-chemotherapy. These results indicate that our nanoplatform may be a promising strategy for targeted combined chemo-photothermal therapy of breast cancer. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • AHA-decorated bifunctionalized HECS-GNR conjugate was developed. • DOX was loaded onto the conjugate via hydrazone linkage. • The conjugate displayed pH-responsive surface charge reversal and drug release. • The conjugate exhibited synergetic photothermal chemotherapy of breast cancer cells. Abstract Chemo-photothermal combination therapy is a promising strategy for cancer treatment. In this study, to achieve the combined photothermal-chemotherapy of breast cancer, a pH-sensitive oxidized hyaluronic acid-decorated dihydroxyphenyl/hydrazide bifunctionalized hydroxyethyl chitosan (DHHC)-gold nanorod (GNR) conjugate was developed. DHHC was synthesized by successive dihydroxyphenylation and hydrazidation of hydroxyethyl chitosan through carbodiimide reaction and click chemistry, respectively. The conjugate was obtained by chemically bonding DHHC onto GNR via Au-catechol bonds. Doxorubicin (DOX) was loaded onto the conjugate via an acid-labile hydrazone linkage with a drug loading content of 5.1%. DOX-loaded conjugate displayed good stability in neutral aqueous solutions and exhibited pH-responsive drug release and surface charge reversal behaviors. In vitro biological studies indicated that the conjugate could be effectively internalized by breast cancer MCF-7 cells and synergistic therapeutic effects were demonstrated, suggesting its great potential in combined photothermal-chemotherapy of breast cancer. [ABSTRACT FROM AUTHOR]

Polysaccharide hydrogels are promising candidate matrices for recapitulating the characteristics of extracellular matrix (ECM) in breast tumors in terms of their structure and composition. Herein, to obtain an ECM-mimetic matrix, hydroxyethyl chitosan (HECS) hydrogels were prepared through Schiff-base crosslinking reaction using dialdehyde hyaluronic acid as crosslinker. The obtained HECS hydrogels displayed a highly porous structure, a stiffness comparable to that of breast tissue, and a fast water-absorption speed. The amount of crosslinker had great effects on the swelling and rheological behaviors of the HECS hydrogels. Preliminary results from in vitro biological assessments confirmed that MCF-7 cells incubated within HECS hydrogels preferred to grow into three-dimensional spheroids. Importantly, the cells displayed enhanced migrative capability and upregulated expression levels of MMP-2, TGF-β and VEGF in comparison to two-dimension cultured cells. Hence, the HECS hydrogels show great promise as a biomimetic ECM in constructing breast tumor models. [ABSTRACT FROM AUTHOR]

Highlights • Multifunctional hyaluronic acid/hydroxyethyl chitosan nanocomplexes were prepared. • DOX and ALA were loaded into polysaccharide nanocomplexes via Schiff base linkage. • Nanocomplexes displayed pH-responsive surface charge reversal and drug release. • Active targeting enhanced additive effect of chemotherapy and photodynamic therapy. Abstract Combination of chemotherapy and photodynamic therapy has emerged as a promising anticancer strategy. Polysaccharide-based nanoparticles are being intensively explored as drug carriers for different forms of combination therapy. In this study, novel multifunctional polysaccharide-based nanocomplexes were prepared from aldehyde-functionalized hyaluronic acid and hydroxyethyl chitosan via sequential self-assembly method. Stable nanocomplexes were obtained through both Schiff's base bond and electrostatic interactions. Chemotherapeutics doxorubicin and pro-photosensitizer 5-aminolevulinic acid were chemically conjugated onto the nanocomplexes via Schiff base linkage. Anti-HER2 antibody as targeting moiety was decorated onto the surface of nanocomplexes. The obtained near-spherical shaped nanocomplexes had an average size of 140 nm and a zeta potential of −24.6 mV, and displayed pH-responsive surface charge reversal and drug release. Active targeting strategy significantly enhanced the cellular uptake of nanocomplexes and combined anticancer efficiency of chemo-photodynamic dual therapy in breast cancer MCF-7 cells. These results suggested that the nanocomplexes had great potential for targeted combination therapy of breast cancer. [ABSTRACT FROM AUTHOR]

Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanovehicle has emerged as a promising combination therapy approach to treating cancers because of their synergistic effect. Nanocarrier delivery systems with low cytotoxicity and high efficiency are needed for such a purpose. In this study, a novel folate-conjugated PEGylated cationic triblock copolymer, poly(acrylhydrazine)- block -poly(3-dimethylaminopropyl methacrylamide)- block -poly(acrylhydrazine) (PAH- b -PDMAPMA- b -PAH), was synthesized and evaluated as a stimuli-sensitive vehicle for the targeted co-delivery of doxorubicin (DOX) and Bcl-2 siRNA into breast cancer MCF-7 cells. The synthetic process of the PEGylated triblock copolymer involved sequential reversible addition-fragmentation chain transfer polymerization, PEGylation and removal of tert -butoxy carbamate protecting groups. Folate-conjugated and/or -unconjugated poly(ethylene glycol) segments were grafted onto PAH- b -PDMAPMA- b -PAH via a reduction-sensitive disulfide linkage. The synthetic polymers were characterized by 1 H NMR and gel permeation chromatography. The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios ≥ 32:1 to form multifunctional nanomicelleplexes. The nanomicelleplexes exhibited spherical shape, possessed a positively charged surface with a zeta potential of + 22.5 mV and had a desirable and uniform particle size of 187 nm. In vitro release studies revealed that the nanomicelleplexes could release DOX and Bcl-2 siRNA in a reduction and pH dual-sensitive manner and the payload release was significantly enhanced in a reductive acidic environment mimicking the endosomes/lysosomes of cancer cells compared to under physiology conditions. Furthermore, the release of both DOX and siRNA was found to follow Higuchi kinetic model. Confocal laser scanning microscopy, flow cytometry and MTT analyses confirmed that, compared with folate-undecorated nanomicelleplexes, folate-decorated nanomicelleplexes could more effectively co-deliver DOX and Bcl-2 siRNA into MCF-7 cells and showed a stronger cell-killing effect. The pristine PEGylated triblock copolymer exhibited good cytocompatibility. Moreover, co-delivery of DOX and Bcl-2 siRNA achieved a significant synergistic antitumor efficacy. These findings suggested that the folate-decorated PEGylated cationic triblock copolymer might be a promising vehicle for targeted intracellular co-delivery of DOX and siRNA in MCF-7 cells, representing a potential clinical combination therapy for breast cancer treatment. [ABSTRACT FROM AUTHOR]

• DOX/CDDP-loaded polysaccharide-based nanovehicles were successfully prepared. • CDDP crosslinking enhanced the stability of NPHER2(DOX/CDDP). • CDDP and DOX were loaded onto AHA by chelation and Schiff's base, respectively. • Nanoparticles composed of drug core and polysaccharide shell were fabricated. • Co-delivery of DOX and CDDP achieved great synergistic anticancer effect. Combination chemotherapy has attracted more and more attention in the field of anticancer treatment. Herein, a synergetic targeted combination chemotherapy of doxorubicin (DOX) and cisplatin in breast cancer was realized by HER2 antibody-decorated nanoparticles assembled from aldehyde hyaluronic acid (AHA) and hydroxyethyl chitosan (HECS). Cisplatin and DOX were successively conjugated onto AHA through chelation and Schiff's base reaction, respectively, forming DOX/cisplatin-loaded AHA inner core. The core was sequentially complexed with HECS and targeting HER2 antibody-conjugated AHA. The formed near-spherical nanoplatform had an average size of ∼160 nm and a zeta potential of −28 mV and displayed pH-responsive surface charge reversal and drug release behaviors. HER2 receptor-mediated active targeting significantly enhanced the cellular uptake of nanoplatform. Importantly, DOX and cisplatin exhibited a synergistic cell-killing effect in human breast cancer MCF-7 cells. These results clearly indicate that the novel nanoplatform is promising for synergistic combination chemotherapy of breast cancer. [ABSTRACT FROM AUTHOR]