Modeling development of breast cancer: from tumor microenvironment to preclinical applications.

Breast cancer is a complex disease and its progression is related not only to tumor cells but also to its microenvironment, which can not be sufficiently reflected by the traditional monolayer cell culture manner. The novel human cancer models comprising tumor microenvironment (TME), such as tumor organoids and organs-on-a-chip, has been established in recent years to help elucidate the underlying mechanisms of tumorigenesis and promote the development of cancer therapies. In this review, we first discuss the current state of breast cancer and their treatment strategies, and elucidates the complex properties of TME of breast cancer .

Biophysical cues of in vitro biomaterials-based artificial extracellular matrix guide cancer cell plasticity.

Clinical evidence supports a role for the extracellular matrix (ECM) in cancer plasticity across multiple tumor types. The lack of in vitro models that represent the native ECMs is a significant challenge for cancer research and drug discovery. Therefore, a major motivation for developing new tumor models is to create the artificial ECM in vitro.

A 3D-printed scaffold-based osteosarcoma model allows to investigate tumor phenotypes and pathogenesis in an in vitro bone-mimicking niche.

Image 1.

Physical confinement in alginate cryogels determines macrophage polarization to a M2 phenotype by regulating a STAT-related mRNA transcription pathway.

The immunologic response is considered to play a pivotal role in the application of biomaterial implants, and intrinsic properties of biomaterials can significantly modulate the anti-inflammatory effects. However, how physical confinement influences M2 polarization of macrophages and the relevant mechanisms have not been clearly elucidated. In this study, pore size and porosity in cryogels can be mediated by utilizing alginates with different viscosities.

Local delivery of biocompatible lentinan/chitosan composite for prolonged inhibition of postoperative breast cancer recurrence.

Postsurgical localized chemotherapy for breast cancer recurrence (BCR) still faces many problems which dampen researchers' enthusiasm and discounted prognosis. Simple strategies with controllable toxicities are expected to address these hurdles. Lentinan (LNT) has excellent biocompatibility and notable antitumor activity but rather low bioavailability after intravenous or oral administration.

Intravital imaging strategy FlyVAB reveals the dependence of Drosophila enteroblast differentiation on the local physiology.

Aging or injury in Drosophila intestine promotes intestinal stem cell (ISC) proliferation and enteroblast (EB) differentiation. However, the manner the local physiology couples with dynamic EB differentiation assessed by traditional lineage tracing method is still vague. Therefore, we developed a 3D-printed platform "FlyVAB" for intravital imaging strategy that enables the visualization of the Drosophila posterior midgut at a single cell level across the ventral abdomen cuticle.

Multiple local therapeutics based on nano-hydrogel composites in breast cancer treatment.

The locoregional recurrence of breast cancer after tumor resection represents several clinical challenges, and conventional post-surgical adjuvant therapeutics always bring about significant systemic side effects. Thus, the local therapy strategy has received considerable interest in breast cancer treatment, and hydrogels can function as ideal platforms due to their remarkable properties such as good biocompatibility, biodegradability, flexibility, and multifunctionality. The nano-hydrogel composites can further incorporate the advantages of nanomaterials into the hydrogel system, to fabricate hierarchical structures for stimulating controlled multi-stage release of different therapeutic agents and improving the synergistic effects of combination therapy.

Biomimetic Matrix Stiffness Modulates Hepatocellular Carcinoma Malignant Phenotypes and Macrophage Polarization through Multiple Modes of Mechanical Feedbacks.

The extracellular matrix (ECM) stiffening is an important sign of local microenvironment change, which is considered as a hallmark of many diseases including hepatocellular carcinoma (HCC). The fates of both cancer cells and immune cells can be regulated by mechanical feedbacks acquired from ECM, but there is a lack of a precise study of mechanical feedback modes in different cell phenotypes following with the progressively increasing ECM stiffness. Herein, we used a biopolymeric film without further modification of adhesive molecules, as a natural local niche to mimic a gradually stiffening manner from HCC onset in liver cirrhosis to its metastasis in the spinal cord.

Immobilized Transforming Growth Factor-Beta 1 in a Stiffness-Tunable Artificial Extracellular Matrix Enhances Mechanotransduction in the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma.

Cancer progression is regulated by multiple factors of extracellular matrix (ECM). Understanding how cancer cells integrate multiple signaling pathways to achieve specific behaviors remains a challenge because of the lack of appropriate models to copresent and modulate ECM properties. Here we proposed a strategy to build a thin biomaterial matrix by poly(l-lysine) and hyaluronan as an artificial stiffness-tunable ECM.

Localized delivery of chemokine for in vitro manipulation of hepatocellular carcinoma cell behaviors during the epithelial-mesenchymal transition.

Hepatocellular carcinoma develops within an altered mechanical and biochemical environment. The chemokine C-X-C motif chemokine ligand 12 plays an important role in tumor cell metastasis during the process of the epithelial-mesenchymal transition. Here, we successfully engineered a biomimetic matrix made up of polyelectrolyte films with appropriate stiffness, which could present C-X-C motif chemokine ligand 12 in an immobilized status in a spatially controlled manner.

Biological responses to nanomaterials: understanding nano-bio effects on cell behaviors.

The unique properties of nanomaterials in drug delivery and tissue engineering have captured a great deal of attention as experimental tools in bioimaging, diagnostic, and therapeutic processes. A plenty of research have provided a strong evidence that nanostructures not only passively interact with cells but also actively engage and mediate cell functions and molecular processes. Undoubtedly, it is crucially important to better understand biological responses to engineered nanomaterials, especially in view of their potential for biomedical applications.

Investigation of the transport and absorption of Angelica sinensis polysaccharide through gastrointestinal tract both in vitro and in vivo.

To investigate the absorption and delivery of ASP in gastrointestinal (GI) tract, cASP was successfully synthesized by chemically modifying with succinic anhydride and then conjugating with a near infrared fluorescent dye Cy5.5. Then, the capacity of oral absorption of cASP was evaluated.

Substrate Stiffness Combined with Hepatocyte Growth Factor Modulates Endothelial Cell Behavior.

Endothelial cells (ECs) play a crucial role in regulating various physiological and pathological processes. The behavior of ECs is modulated by physical (e.g.

Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth.

The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors.

Multiple functional hyperbranched poly(amido amine) nanoparticles: synthesis and application in cell imaging.

The hyperbranched poly(amido amine) nanoparticles (HPAMAM NPs) with multiple functions, such as biodegradability, autofluorescence, and specific affinity, were successfully prepared by Michael addition dispersion polymerization of CBA, AEPZ, and N-galactosamine hydrochloride (or N-glucosamine hydrochloride) in a mixture of methanol/water. The resultant NPs displayed strong photoluminescence, high photostability, broad absorption, and emission (from 430 to 620 nm) spectra. The fluorescence from HPAMAM NPs may be attributed to the tertiary amine chromophore.

Targeted delivery of antisense inhibitor of miRNA for antiangiogenesis therapy using cRGD-functionalized nanoparticles.

MiRNAs are viable therapeutic targets for cancer therapy, but the targeted delivery of miRNA or its anti-miRNA antisense oligonucleotides (AMOs) remains a challenge. We report here a PEGylated LPH (liposome-polycation-hyaluronic acid) nanoparticle formulation modified with cyclic RGD peptide (cRGD) for specific and efficient delivery of AMO into endothelial cells, targeting α(v)β₃ integrin present on the tumor neovasculature. The nanoparticles effectively delivered anti-miR-296 AMO to the cytoplasm and downregulated the target miRNA in human umbilical vein endothelial cells (HUVECs), which further efficiently suppressed blood tube formulation and endothelial cell migration, owing to significant upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), whereas nanoparticles without cRGD modification showed only little AMO uptake and miRNA silencing activity.

Brush-shaped polycation with poly(ethylenimine)-b-poly(ethylene glycol) side chains as highly efficient gene delivery vector.

A brush-shaped polymer PHEMA-g-(PEI-b-PEG) with poly(2-hydroxyethyl methacrylate) (PHEMA) backbone and linear poly(ethylenimine)-b-poly(ethylene glycol) (PEI-b-PEG) side chains was synthesized and evaluated as a vector for potential cancer gene therapy. The characterizations by (1)H NMR and laser light scattering demonstrated the brush structure of the polymer. PHEMA-g-(PEI-b-PEG) was much less cytotoxic when compared with branched poly(ethylenimine) with M(w) of 25 kDa.

Gold nanoparticles stabilized by thermosensitive diblock copolymers of poly(ethylene glycol) and polyphosphoester.

Aqueous dispersions of thermosensitive gold nanoparticles protected by diblock copolymers of poly(ethylene glycol) and polyphosphoester were prepared and studied. Diblock copolymers MPEG-b-P(EEP-co-PEP) with different compositions that are composed of monomethoxy poly(ethylene glycol), random copolymer of ethyl ethylene phosphate (EEP), and isopropyl ethylene phosphate (PEP) were synthesized by ring-opening polymerization in bulk. Thioctic acid was then conjugated to the terminal hydroxyl group of the polyphosphoester block by esterification.

Functionalized micelles from block copolymer of polyphosphoester and poly(epsilon-caprolactone) for receptor-mediated drug delivery.

Cellular specific micellar systems from functional amphiphilic block copolymers are attractive for targeted intracellular drug delivery. In this study, we developed reactive micelles based on diblock copolymer of poly(ethyl ethylene phosphate) and poly(epsilon-caprolactone). The micelles were further surface conjugated with galactosamine to target asialoglycoprotein receptor (ASGP-R) of HepG2 cells.