An Implantable Active-Targeting Micelle-in-Nanofiber Device for Efficient and Safe Cancer Therapy

Nanocarriers have attracted broad attention in cancer therapy because of their ability to carry drugs preferentially into cancer tissue, but their application is still limited due to the systemic toxicity and low delivery efficacy of intravenously delivered chemotherapeutics. In this study, we develop a localized drug delivery device with combination of an active-targeting micellar system and implantable polymeric nanofibers. This device is achieved first by the formation of hydrophobic doxorubicin (Dox)-encapsulated active-targeting micelles assembled from a folate-conjugated PCL–PEG copolymer. Then, fabrication of the core–shell polymeric nanofibers is achieved with coaxial electrospinning in which the core region consists of a mixture of poly(vinyl alcohol) and the micelles and the outer shell layer consists of cross-linked gelatin. In contrast to the systematic administration of therapeutics <i>via</i> repeatedly intravenous injections of micelles, this implantable device has these capacities of greatly reducing the drug dose, the frequency of administration and side effect of chemotherapeutic agents while maintaining highly therapeutic efficacy against artificial solid tumors. This micelle-based nanofiber device can be developed toward the next generation of nanomedicine for efficient and safe cancer therapy

Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles

Highly effective delivery of therapeutic agents into target cells using nanocarriers and subsequently rapid intracellular release are of great importance in cancer treatment. Here, we developed an enzyme and redox dual-responsive polymeric micelle with active targeting abilities to achieve rapid intracellular drug release. To overcome both its poor solubility in water and instability in the blood circulation, camptothecin (CPT) was chemically conjugated to monomethyl poly­(ethylene glycol) (mPEG) via a redox-responsive linker to form polymeric prodrugs. The enzyme-responsive function is achieved by connecting hydrophobic polycaprolactone segments and hydrophilic PEG segments with azo bonds. Additionally, the end of the PEG segment was decorated with phenylboronic acid (PBA), endowing the nanocarriers with active targeting abilities. The dual-responsive targeting polymeric micelles can be generated by self-assembly of a mixture of the polymeric prodrug and enzyme-responsive copolymer. The <i>in vitro</i> drug release profile revealed that CPT was rapidly released from the micelles under a simulated condition similar to the tumor cell microenvironment. <i>In vivo</i> and <i>ex vivo</i> fluorescence imaging indicated that these micelles possess excellent specificity to target hepatoma carcinoma cells. The antitumor effect in mice liver cancer cells (H22) in tumor-bearing Kunming (KM) mice demonstrated that this nanocarrier exhibits high therapeutic efficiency in artificial solid tumors and low toxicity to normal tissues, with a survival rate of approximately 100% after 160 days of treatment

Bioinspired 3D Multilayered Shape Memory Scaffold with a Hierarchically Changeable Micropatterned Surface for Efficient Vascularization

How to achieve three-dimensional (3D) cell alignment and subsequent prompt tissue regeneration remains a great challenge. Here, inspired by the interior 3D architecture of native arteries, we develop a new 3D multilayered shape memory vascular scaffold with a hierarchically changeable micropatterned surface for vascularization. The shape memory function renders the implantation of the scaffold safe and convenient via minimally invasive surgery. By co-culturing endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) on the 3D multilayered structure, the inner monolayer, which has a square micropatterned surface, can promote EC adhesion and migration, resulting in a rapid endothelialization, and the outer multilayers, which have rectangular micropatterned surfaces, can induce a circumferential alignment of VSMCs. After implantation in the cervical artery of a New Zealand rabbit for 120 days, the graft developed a high capacity for modulating cellular 3D alignment, to generate a neonatal functional blood vessel with an endothelium layer in the inner layer and multilevel VSMC circumferential alignments in the outer layers

Light-Activated ROS-Responsive Nanoplatform Codelivering Apatinib and Doxorubicin for Enhanced Chemo-Photodynamic Therapy of Multidrug-Resistant Tumors

Clinical chemotherapy confronts a challenge resulting from cancer-related multidrug resistance (MDR), which can directly lead to treatment failure. To address it, an innovative approach is proposed to construct a light-activated reactive oxygen species (ROS)-responsive nanoplatform based on a protoporphyrin (PpIX)-conjugated and dual chemotherapeutics-loaded polymer micelle. This system combines chemotherapy and photodynamic therapy (PDT) to defeat the MDR of tumors. Such an intelligent nanocarrier can prolong the circulation time in blood because of the negative polysaccharide component of chondroitin sulfate, and subsequently being selectively internalized by MCF-7/ADR cells [doxorubicin (DOX)-resistant]. When exposed to 635 nm red light, this nanoplatform generates sufficient ROS through the photoconversion of PpIX, further triggering the disassociation of the micelles to release the dual cargoes. Afterward, the released apatinib, serving as a reversal inhibitor of MDR, can recover the chemosensitivity of DOX by competitively inhibiting the P-glycoprotein drug pump in drug-resistant tumor cells, and the excessive ROS has a strong capacity to exert its PDT effect to act on the mitochondria or the nuclei, ultimately causing cell apoptosis. As expected, this intelligent nanosystem successfully reverses tumor MDR via the synergism between apatinib-enhanced DOX sensitivity and ROS-mediated PDT performance

Flexible Polymer Ultra-Fine Fiber with Extreme Toughness

Fiber materials with multilevel interior structures have myriad applications in many fields due to their unique properties. In this study, we develop a bioinspired flexible ultrafine polymer fiber via an integrated microfluidic-electrospinning technology. The fiber possesses periodic hollow and tubular chambers with a shell layer of approximately 150 nm in thickness extremely like natural bamboo. The single fiber with a diameter of ∼1.5 μm exhibits the Young’s modulus ranging from 2 to 7 MPa measured with atomic force microscopy (AFM). The fiber with periodic hollow chambers and extreme toughness can find many applications in medicine, industry, and agriculture

Triple Shape Memory Effect of Star-Shaped Polyurethane

In this study, we synthesized one type of star-shaped polyurethane (SPU) with star-shaped poly­(ε-caprolactone) (SPCL) containing different arm numbers as soft segment and 4,4′-diphenyl methane diisocyanate (MDI) as well as chain extender 1,4-butylene glycol (BDO) as hard segment. Proton nuclear magnetic resonance (¹H-NMR) confirmed the chemical structure of the material. Differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) results indicated that both the melting temperature (<i>T</i>_m) and transition temperature (<i>T</i>_trans) of SPU decreased with the hard segment composition increase. X-ray diffraction (XRD) results demonstrated that the increase of the crystallinity of SPU following the raised arm numbers endowed a high shape fixity of six-arm star-shaped polyurethane (6S-PU) and a wide melting temperature range, which resulted in an excellent triple-shape memory effect of 6S-PU. The in vitro cytotoxicity assay evaluated with osteoblasts through Alamar blue assay demonstrates that this copolymer possessed good cytocompatibility. This material can be potentially used as a new smart material in the field of biomaterials

pH-Responsive Shape Memory Poly(ethylene glycol)–Poly(ε-caprolactone)-based Polyurethane/Cellulose Nanocrystals Nanocomposite

In this study, we developed a pH-responsive shape-memory polymer nanocomposite by blending poly­(ethylene glycol)–poly­(ε-caprolactone)-based polyurethane (PECU) with functionalized cellulose nanocrystals (CNCs). CNCs were functionalized with pyridine moieties (CNC–C₆H₄NO₂) through hydroxyl substitution of CNCs with pyridine-4-carbonyl chloride and with carboxyl groups (CNC–CO₂H) via 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) mediated surface oxidation, respectively. At a high pH value, the CNC–C₆H₄NO₂ had attractive interactions from the hydrogen bonding between pyridine groups and hydroxyl moieties; at a low pH value, the interactions reduced or disappeared due to the protonation of pyridine groups, which are a Lewis base. The CNC–CO₂H responded to pH variation in an opposite manner. The hydrogen bonding interactions of both CNC–C₆H₄NO₂ and CNC–CO₂H can be readily disassociated by altering pH values, endowing the pH-responsiveness of CNCs. When these functionalized CNCs were added in PECU polymer matrix to form nanocomposite network which was confirmed with rheological measurements, the mechanical properties of PECU were not only obviously improved but also the pH-responsiveness of CNCs could be transferred to the nanocomposite network. The pH-sensitive CNC percolation network in polymer matrix served as the switch units of shape-memory polymers (SMPs). Furthermore, the modified CNC percolation network and polymer molecular chains also had strong hydrogen bonding interactions among hydroxyl, carboxyl, pyridine moieties, and isocyanate groups, which could be formed or destroyed through changing pH value. The shape memory function of the nanocomposite network was only dependent on the pH variation of the environment. Therefore, this pH-responsive shape-memory nancomposite could be potentially developed into a new smart polymer material

Precise Polymerization of a Highly Tumor Microenvironment-Responsive Nanoplatform for Strongly Enhanced Intracellular Drug Release

The importance of achieving a high content of responsive groups of drug carriers is well-known for achieving rapid intracellular drug release; however, very little research has been published on this subject. Here, we present an entirely new strategy to synthesize a highly reduction-sensitive polymer-drug conjugate with one disulfide bond corresponding to each resultant copolymer through a precise ring-opening polymerization of ε-caprolactone that is initiated by a monoprotected cystamine. Simultaneously, the anticancer drug doxorubicin is chemically conjugated to the polymer via pH-responsive hydrazone bonds, which effectively prevent premature drug release in the blood circulation. The 3-aminophenylboronic acid (PBA) targeting ligands endow an active-targeting ability that significantly prompts the specific internalization of nanocarriers by tumor cells and thus results in excellent cytotoxicity against tumor cells. The concept of precise polymerization is put forward to achieve multifunctional nanocarriers for the first time. This study is expected to inspire the development of a highly environment-responsive nanoplatform for drug delivery in future clinical applications

Thermo-triggered Drug Release from Actively Targeting Polymer Micelles

How to deliver the drug to the target area at the right time and at the right concentration is still a challenge in cancer therapy. In this study, we present a facile strategy to control drug release by precisely controlling the thermo-sensitivity of the nanocarriers to the variation of environmental temperature. One type of thermoresponsive Pluronic F127-poly­(d,l-lactic acid) (F127-PLA, abbreviated as FP) copolymer micelles was developed and decorated with folate (FA) for active targeting. FP100 micelles assembled from FP with PLA segment having polymerization degree of 100 had a low critical solution temperature of 39.2 °C close to body temperature. At 37 °C, little amount of encapsulated anticancer drug DOX is released from the FP100 micelles, while at a slightly elevated temperature (40 °C), the shrinkage of thermoresponsive segments causes a rapid release of DOX and instantly increases the drug concentration locally. The cytocompatibility analysis and cellular uptake efficiency were characterized with the fibroblast cell line NIH 3T3 and human cervix adenocarcinoma cell line HeLa. The results demonstrate that this copolymer has excellent cytocompatibility, and FA-decorated FP100 micelles present much better efficiency of cellular uptake and higher cytotoxicity to folate receptor (FR)-overexpressed HeLa cells. In particular, under hyperthermia (40 °C) the cytotoxicity of DOX-loaded FA-FP100 micelles against HeLa cells was significantly more obvious than that upon normothermia (37 °C). Therefore, these temperature-responsive micelles have great potential as a drug vehicle for cancer therapy

Supercooling Self-Assembly of Magnetic Shelled Core/Shell Supraparticles

Molecular self-assembly has emerged as a powerful technique for controlling the structure and properties of core/shell structured supraparticles. However, drug-loading capacities and therapeutic effects of self-assembled magnetic core/shell nanocarriers with magnetic nanoparticles in the core are limited by the intervention of the outer organic or inorganic shell, the aggregation of superparamagnetic nanoparticles, the narrowed inner cavity, etc. Here, we present a self-assembly approach based on rebalancing hydrogen bonds between components under a supercooling process to form a new core/shell nanoscale supraparticle with magnetic nanoparticles as the shell and a polysaccharide as a core. Compared with conventional iron oxide nanoparticles, this magnetic shelled core/shell nanoparticle possesses an optimized inner cavity and a loss-free outer magnetic property. Furthermore, we find that the drug-loaded magnetic shelled nanocarriers showed interesting <i>in vitro</i> release behaviors at different pH conditions, including “swelling-broken”, “dissociating-broken”, and “bursting-broken” modes. Our experiments demonstrate the novel design of the multifunctional hybrid nanostructure and provide a considerable potential for the biomedical applications