Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel.

BACKGROUND: Breast cancer negatively affects women's health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell-cell and cell-matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers. METHODS: Chitosan can be modified to construct three-dimensional (3D) tumour models. Here, we report an in vitro 3D tumour model using a hydroxyethyl chitosan/glycidyl methacrylate (HECS-GMA) hydrogel produced by a series of chitosan modifications. Parameters relating to cell morphology, viability, proliferation, and migration were analysed using breast cancer MCF-7 cells. In a xenograft model, secretion of angiogenesis-related growth factors and the anti-angiogenic efficacy of Endostar and Bevacizumab in cells grown in HECS-GMA hydrogels were assessed by immunohistochemistry. RESULTS: Hydroxyethyl chitosan/glycidyl methacrylate hydrogels had a highly porous microstructure, mechanical properties, swelling ratio, and morphology consistent with a 3D tumour model. Compared with a 2D monolayer culture, breast cancer MCF-7 cells residing in the HECS-GMA hydrogels grew as tumour-like clusters in a 3D formation. In a xenograft model, MCF-7 cells cultured in the HECS-GMA hydrogels had increased secretion of angiogenesis-related growth factors. Recombinant human endostatin (Endostar), but not Bevacizumab (Avastin), was an effective anti-angiogenic agent in HECS-GMA hydrogels. CONCLUSIONS: The HECS-GMA hydrogel provided a 3D tumour model that mimicked the in vivo cancer microenvironment and supported the growth of MCF7 cells better than traditional tissue culture plates. The HECS-GMA hydrogel may offer an improved platform to minimize the gap between traditional tissue culture plates and clinical applicability. In addition, the anti-angiogenic efficacy of drugs such as Endostar and Bevacizumab can be more comprehensively studied and assessed in HECS-GMA hydrogels.

SET7/9 inhibits oncogenic activities through regulation of Gli-1 expression in breast cancer.

SET7/9 is a protein lysine methyltransferase that had been initially identified as a histone lysine methyltransferase which generates monomethylation at histone 3 lysine 4. Different functions were attributed to the protein methylation mediated by SET7/9. In this study, we found that the expression of SET7/9 declined in a majority of the human breast cancer tissues examined compared with normal tissues. Knockdown of SET7/9 promoted the proliferation, migration, and invasion of breast cancer cells. Knockdown of SET7/9 also increased the tumorigenicity of breast cancer cells in vivo. On the contrary, overexpression of SET7/9 in breast cancer cells inhibited these processes. Microarray analysis indicated that Gli-1 may play function as a downstream factor of SET7/9. Overexpression of SET7/9SET7/9 inhibits Gli-1 expression. While knockdown of SET7/9 promotes the expression of Gli-1. Gli-1 inhibited by cyclopamine blocked knockdown SET7/9-driven proliferation, migration, and invasion in breast cancer cell. Furthermore, Gli-1 expression in human breast cancer tissues is negatively correlated with SET7/9 expression. Together, these results helped to realize the antioncogene functions of SET7/9 in breast cancer cells and provided a novel direction to treat breast cancer.

Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells.

The present study was to examine the effect of Tripartite motif 16 (TRIM16) on epithelial-mesenchymal transition (EMT) and metastasis in non-small cell lung cancer (NSCLC) cells, and its clinical significance in NSCLC. The correlation of TRIM16 expression and clinical features of NSCLC was analyzed in paraffin-embedded archived normal lung tissues and NSCLC tissues by immunohistochemical analysis. The effect of TRIM16 on EMT and metastasis was examined both in vitro and in vivo. The expression of TRIM16 was markedly decreased in NSCLC and correlated with tumor metastasis. Upregulation of TRIM16 significantly inhibited EMT and metastasis of NSCLC cells. In contrast, silencing TRIM16 expression significantly promoted the EMT and metastasis of NSCLC cells both in vitro and in vivo. Moreover, we demonstrated that downregulation of TRIM16 activated the sonic hedgehog pathway, and that inhibition of the sonic hedgehog pathway by cyclopamine abrogated the effect of TRIM16-downregulation induced EMT and metastasis on NSCLC cells. Our results suggest that TRIM16 is a potential pharmacologic target for the treatment of NSCLC and promotion TRIM16 expression might represent a novel strategy to NSCLC metastasis.

GATA6 is overexpressed in breast cancer and promotes breast cancer cell epithelial-mesenchymal transition by upregulating slug expression.

Metastasis is the leading cause of death in breast cancer (BC) patients. However, until now, the mechanisms of BC metastasis remain elusive. GATA6 is a member of the GATA transcription factor family that plays critical regulatory roles in tissue development, which has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in BC remain unclear. Here we show that GATA6 is elevated in BC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of GATA6 was associated with decreased overall survival of BC patients. Overexpression of GATA6 in BC cells increased epithelial-mesenchymal transition. In contrast, silencing GATA6 in aggressive BC cells inhibited this process. Mechanistically, we found GATA6 exerts its function through active slug transcription. Slug knockdown blocked the GATA6-driven EMT. Furthermore, slug expression in human BC is positively correlated with GATA6 expression. Our results, for the first time, portray a pivotal role of GATA6 in regulating metastatic behaviors of BC cells, suggesting GATA6 is a potential therapeutic target in metastatic BCs.

Hyaluronan-decorated copper-doxorubicin-anlotinib nanoconjugate for targeted synergistic chemo/chemodynamic/antiangiogenic tritherapy against hepatocellular carcinoma.

Copper-based nanomaterials show considerable potential in the chemodynamic therapy of cancers. However, their clinical application is restricted by low catalytic activity in tumor microenvironment and copper-induced tumor angiogenesis. Herein, a novel copper-doxorubicin-anlotinib (CDA) nanoconjugate was constructed by the combination of copper-hydrazide coordination, hydrazone linkage and Schiff base bond. The CDA nanoconjugate consists of a copper-3,3'-dithiobis(propionohydrazide)-doxorubicin core and an anlotinib-hyaluronan shell. Benefiting from hyaluronan camouflage and abundant disulfide bonds and Cu2+, the CDA nanoconjugate possessed excellent tumor-targeting and glutathione-depleting abilities and enhanced chemodynamic efficacy. Released doxorubicin significantly improved copper-mediated chemodynamic therapy by upregulating nicotinamide adenine dinucleotide phosphate oxidase 4 expression to increase intracellular H2O2 level. Furthermore, the nanoconjugate produced excessive •OH to induce lipid peroxidation and mitochondrial dysfunction, thus greatly elevating doxorubicin-mediated chemotherapy. Importantly, anlotinib effectively inhibited the angiogenic potential of copper ions. In a word, the CDA nanoconjugate is successfully constructed by combined coordination and pH-responsive linkages, and displays the great potential of copper-drug conjugate for targeted synergistic chemo/chemodynamic/antiangiogenic triple therapy against cancers.

[Retracted] Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli­1 degradation via the ubiquitin­proteasome pathway.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that the data obtained from sphere­forming assay experiments shown in Figs. 4C­F and 8B and C, and western blotting data in Figs. 4A and 8A, were strikingly similar to data appearing in different form in other articles by different authors from different research institutes that had already been published, one of which has been retracted. Moreover, a pair of data panels comparing between Fig. 4E and 8C were partly overlapping, such that these data appear to have been derived from the same original source. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1204­1212, 2016; DOI: 10.3892/or.2015.4437].

Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper-dithiocarbamate chelate-doped and artemisinin-loaded hollow nanoplatform (HNP) is developed via a chelation competition-induced hollowing strategy for cuproptosis-based combination therapy. The HNP exhibits tumor microenvironment-triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2 O2 to produce C-centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds-rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S-acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate-copper chelate-mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.

Hydrazide/Metal/Indocyanine Green Coordinated Nanoplatform for Potentiating Reciprocal Ferroptosis and Immunity against Melanoma.

Ferroptosis holds great potential in cancer treatment, but its efficacy is severely limited by a low Fenton reaction efficacy. Meanwhile, the interactive relationship between Ferroptosis and the PD-1 blockade is still vague. Herein, a hydrazide/Cu/Fe/indocyanine green coordinated nanoplatform (TCFI) is constructed by a hydrazide-metal-sulfonate coordination process. The TCFI nanoplatform exhibits Fenton-/catalase-/glutathione oxidase-like triple activities and accordingly can trigger lipid peroxidation, relieve hypoxia, and downregulate the glutathione/glutathione peroxidase 4 axis, thus achieving positively and negatively dually enhanced Ferroptosis in B16F10 cancer cells. Under near-infrared laser irradiation, the TCFI nanoplatform induces robust immunogenic cancer cell death by elevating the intracellular reactive oxygen species level through synergistic photodynamic therapy/Ferroptosis, which significantly potentiates CD8+ T cell infiltration into tumors and interferon-γ secretion. Moreover, upregulated interferon-γ efficiently inhibits system xc- activity and sensitizes cancer cells to Ferroptosis. Interestingly, the PD-1 blockade may strengthen the reciprocal process. The combination of the TCFI nanoplatform and αPD-1 can eliminate primary tumors and inhibit distant tumor growth, lung metastasis, and tumor recurrence. This study presents a simple and novel coordination strategy to fabricate tumor microenvironment-responsive nanodrugs and highlights the enhancement effect of photodynamic therapy on reciprocal Ferroptosis and antitumor immunity.

Photo-crosslinked hyaluronic acid hydrogel as a biomimic extracellular matrix to recapitulate in vivo features of breast cancer cells.

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.

Hydrazided hyaluronan/cisplatin/indocyanine green coordination nanoprodrug for photodynamic chemotherapy in liver cancer.

It is still a huge challenge for concurrent highly efficient loading of chemotherapeutic agent and photosensitizer into single nanocarrier via stimuli-responsive linkages due to their different physicochemical properties and pharmacokinetics. Herein, based on the discovery of unique cisplatin-hydrazide and cisplatin-indocyanine green (ICG) coordination reactions, a multifunctional coordination nanoprodrug, cisplatin/ICG co-loaded hydrazided hyaluronan/bovine serum albumin (HBCI) nanoparticles, was developed by a desolvation-dual coordination process. The nanoprodrug exhibited ultrahigh drug loading efficiency and glutathione/NIR light dual-responsive drug release behavior. In vitro cellular studies demonstrated efficient internalization and apoptosis-inducing ability of the nanoprodrug in HepG2 cells. In vivo results confirmed the efficacious tumor accumulation and biosafety of HBCI nanoprodrug and synergistic effect of HBCI-based combined photodynamic chemotherapy on inhibiting tumor growth. Overall, this work not only provides a novel dual coordination approach for highly efficient loading of cisplatin and ICG but also verifies the therapeutic potential of HBCI nanoprodrug in combating hepatocellular carcinoma.

Injectable hyaluronan/MnO2 nanocomposite hydrogel constructed by metal-hydrazide coordinated crosslink mineralization for relieving tumor hypoxia and combined phototherapy.

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/MnO2 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 H2O2 into O2 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 O2-enhanced efficient topical dual-phototherapy of breast cancer.

Hydrazide-manganese coordinated multifunctional nanoplatform for potentiating immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H2O2 to O2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment.

Hydroxyethyl chitosan hydrogels for enhancing breast cancer cell tumorigenesis.

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-ß 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.

HER2 immunohistochemistry staining positivity is strongly predictive of tumor response to neoadjuvant chemotherapy in HER2 positive breast cancer.

BACKGROUND: The current recommendation is to reflex test HER2 immunohistochemistry (IHC) equivocal breast cancer cases with fluorescence in situ hybridization (FISH) analysis. Either IHC 3+ or FISH positive cancers are considered HER2 positive (HER2+) and treated with HER2 targeted therapy. This study examined the predictive value of HER IHC or FISH positivity in tumor response to HER2 targeted therapy. METHODS: Biopsies of 76 HER2+ breast cancer cases were evaluated. All patients were treated with neoadjuvant HER2 targeted therapy and chemotherapy. Tumor response was evaluated on the excisional specimens. Cancers with complete pathologic response (pCR) or MD Anderson residual cancer burden-I (RCB-I) were classified as responders and cancers with RCB-II/III as non-responders. Clinicopathologic parameters were correlated with response. RESULTS: In univariate analysis, small tumor size, low nuclear grade, high Ki67, HER2 IHC 3+, homogenous strong HER2 IHC staining, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with pCR/RCB-I. In multivariate analysis, homogenous strong HER2 IHC staining pattern was significantly associated with pCR/RCB-I. The receiver operating characteristics (ROC) model showed either high HER2/CEP17 ratio or HER2 copy number individually was predictive of tumor response. CONCLUSION: HER2 IHC staining pattern is significantly associated with tumor response to neoadjuvant chemotherapy, reiterating the importance of HER2 IHC evaluation. The ROC model shows either high HER2/CEP17 ratio or high HER2 copy number individually is predictive of tumor response to neoadjuvant HER2 targeted therapy in HER2+ breast cancer.

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2-Directed Chemotherapy in HER2-Positive Breast Cancer.

BACKGROUND: HER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2+ breast cancer. PATIENTS AND METHODS: Patients with HER2+ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio. RESULTS: Small tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses. CONCLUSION: Clinicopathologic features may help predict HER2+ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.

NIR/pH dual-responsive polysaccharide-encapsulated gold nanorods for enhanced chemo-photothermal therapy of breast cancer.

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.

Dual-degradable and injectable hyaluronic acid hydrogel mimicking extracellular matrix for 3D culture of breast cancer MCF-7 cells.

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.

Multifunctional PEG-b-polypeptide-decorated gold nanorod for targeted combined chemo-photothermal therapy of breast cancer.

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.

Doxorubicin/cisplatin co-loaded hyaluronic acid/chitosan-based nanoparticles for in vitro synergistic combination chemotherapy of breast cancer.

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.

Sequentially self-assembled polysaccharide-based nanocomplexes for combined chemotherapy and photodynamic therapy of breast cancer.

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.