Near‐Infrared Absorbing Polymeric Nanoparticles as a Versatile Drug Carrier for Cancer Combination Therapy

Poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PEDOT:PSS) nanoparticles, after being coated with polyethylene glycol (PEG), are used as a drug carrier to load various types of aromatic therapeutic molecules, including chemotherapy drugs doxorubicin (DOX) and SN38, as well as a photodynamic agent chlorin e6 (Ce6), through π–π stacking and hydrophobic interaction. Interesting functionalities of PEDOT:PSS‐PEG as an unique versatile drug delivery platform are discovered. Firstly, for water‐insoluble drugs such as SN38, the loading on PEDOT:PSS‐PEG dramatically enhances its water solubility, while maintaining its cytotoxicity to cancer cells. Secondly, the delivery of Ce6 by PEDOT:PSS‐PEG is able to remarkably accelerate the cellular uptake of Ce6 molecules, and thus offers improved photodynamic therapeutic efficacy. Using DOX‐loaded PEDOT:PSS‐PEG as the model system, it is demonstrated that the photothermal effect of PEDOT:PSS‐PEG can be utilized to promote the delivery of this chemotherapeutic agent, achieving a combined photothermal‐ and chemotherapy with an obvious synergistic cancer killing effect. Moreover, it is also shown that multiple types of therapeutic agents could be simultaneously loaded on PEDOT:PSS‐PEG nanoparticles and delivered into cancer cells. This work highlights the great potential of NIR‐absorbing polymeric nanoparticles as multifunctional drug carriers for potential cancer combination therapy with high efficacy.     

Biofunctional Polyelectrolyte Multilayers and Microcapsules: Control of Non‐Specific and Bio‐Specific Protein Adsorption

Layers of the polyelectrolytes poly(allylamine hydrochloride) (PAH, polycationic) and poly(styrene sulfonate) (PSS, polyanionic) are consecutively adsorbed on flat silicon oxide surfaces, forming stable, ultrathin multilayer films. Subsequently, a final monolayer of the polycationic copolymer poly(L ‐lysine)‐graft‐poly(ethylene glycol) (PLL‐g‐PEG) is adsorbed onto the PSS‐terminated multilayer in order to impart protein resistance to the surface. The growth of each of the polyelectrolyte layers and the protein resistance of the resulting [PAH/PPS]_n(PLL‐g‐PEG) multilayer (n = 1–4) are followed quantitatively ex situ using X‐ray photoelectron spectroscopy and in situ using real‐time optical‐waveguide lightmode spectroscopy. In a second approach, the same type of [PAH/PSS]_n(PLL‐g‐PEG) multilayer coatings are successfully formed on the surface of colloidal particles in order to produce surface‐functionalized, hollow microcapsules after dissolution of the core materials (melamine formaldehyde (MF) and poly(lactic acid) (PLA; colloid diameters: 1.2–20 μm). Microelectrophoresis and confocal laser scanning microscopy are used to study multilayer formation on the colloids and protein resistance of the final capsule. The quality of the PLL‐g‐PEG layer on the microcapsules depends on both the type of core material and the dissolution protocols used. The greatest protein resistance is achieved using PLA cores and coating the polyelectrolyte microcapsules with PLL‐g‐PEG after dissolution of the cores. Protein adsorption from full serum on [PAH/PPS]_n(PLL‐g‐PEG) multilayers (on both flat substrates and microcapsules) decreases by three orders of magnitude in comparison to the standard [PAH/PPS]_n layer. Finally, biofunctional capsules of the type [PAH/PPS]_n(PLL‐g‐PEG/PEG‐biotin) (top copolymer layer with a fraction of the PEG chains end‐functionalized with biotin) are produced which allow for specific recognition and immobilization of controlled amounts of streptavidin at the surface of the capsules. Biofunctional multilayer films and capsules are believed to have a potential for future applications as novel platforms for biotechnological applications such as biosensors and carriers for targeted drug delivery.     

Multifunctional Nanoparticles Composed of A Poly( dl‐lactide‐coglycolide) Core and A Paramagnetic Liposome Shell for Simultaneous Magnetic Resonance Imaging and Targeted Therapeutics

A multifunctional nanoscale platform that is self‐assembled from a hydrophobic poly( dl ‐lactide‐coglycolide)(PLGA) core and a hydrophilic paramagnetic‐folate‐coated PEGylated lipid shell (PFPL; PEG=polyethylene glycol) is designed for simultaneous magnetic resonance imaging (MRI) and targeted therapeutics. The nanocomplex has a well‐defined core‐shell structure which is studied using confocal laser scanning microscopy (CLSM). The paramagnetic diethylenetriaminepentaacetic acid‐gadolinium (DTPA‐Gd) chelated to the shell layer exhibits significantly higher spin–lattice relaxivity (r₁) than the clinically used small‐molecular‐weight MRI contrast agent Magnevist^®. The PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From a drug‐release study, it is found that the modification of the PLGA core with a polymeric liposome shell can be a useful tool for reducing the drug‐release rate. Cellular uptake of folate nanocomplex is found to be higher than that of non‐folate‐nanocomplex due to the folate‐binding effect on the cell membrane. This work indicates that the multifunctional platform with combined characteristics applicable to MRI and drug delivery may have great potential in cancer chemotherapy and diagnosis.     

Peptide‐Enhanced Selective Surface Deposition of Polymer‐Based Fragrance Delivery Systems

Surface deposition is a critical step in the application of fragrance‐containing products. This contribution presents a novel strategy to enhance the deposition of polymer‐based fragrance delivery systems onto cotton substrates from the application medium using phage display identified peptides. Following the identification of cotton binding peptide ligands under fabric softening conditions via phage display, the strongest binding peptide ligand is incorporated into two model polymer‐based fragrance delivery systems, viz., polymer profragrances and polymer nanoparticles. The model polymer profragrance used is a linear, water soluble poly(N‐(2‐hydroxypropyl)methacrylamide) conjugate, while poly(styrene‐co‐acrylic acid) (PS‐co‐PAA) nanoparticles prepared via miniemulsion polymerization are chosen as the second model system. The incorporation of the cotton binding peptide ligand into these fragrance delivery systems enhances their surface deposition two‐ to three‐fold, as evidenced by fluorescence intensity measurements. In the case of the fragrance‐containing PS‐co‐PAA nanoparticles, the enhanced surface deposition also translates into an increased fragrance release from the cotton surface according to dynamic headspace sampling measurements.     

Light‐Responsive,Singlet‐Oxygen‐Triggered On‐Demand Drug Release from Photosensitizer‐Doped Mesoporous Silica Nanorods for Cancer Combination Therapy

Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Steric Protected and Illumination‐Activated Tumor Targeting Accessory for Endowing Drug‐Delivery Systems with Tumor Selectivity

Here, an ABA‐typed polymer, octadecyl‐polyethylene glycol (biotin)‐(o‐nitrobenzyl)‐octadecyl ester (CPB‐p‐C) with an o‐nitrobenzyl group inserted between polyethylene glycol (PEG) and octadecyl ester is synthesized as an illumination‐activated tumor targeting accessory for micelle‐based drug carriers. The functional accessory can form a flower‐like structure with folded PEG segments in aqueous solution to hide targeting biotin ligands in the core of the mixed micelle. Thus the specific binding between biotin and avidin can be suppressed by the steric hindrance of PEG shell. Upon illumination, the flower‐like structure of CPB‐p‐C is destroyed due to the cleavage of the o‐nitrobenzyl group and the biotin moieties are exposed on the surface of the micelle through the stretching process of PEG segments, generating ligand‐receptor‐mediated targeted delivery. By confocal laser scanning microscopy and flow cytometry, the illumination‐activated, tumor‐targeting delivery is studied. The influence of the amount of functional accessory in the mixed micelle on the targeting property is investigated and the optimal amount of CPB‐p‐C to achieve less side effects and better illumination activated tumor targeting activity is identified. The observed properties of CPB‐p‐C qualify it as a promising functional accessory to endow traditional drug‐delivery systems with tumor selectivity.     

Delivery of Nucleic Acids through the Controlled Disassembly of Multifunctional Nanocomplexes

In this study, novel pH‐responsive polyion complex micelles (PICMs) were developed for the efficient delivery of nucleic acid drugs, such as antisense oligonucleotide (AON) and short interfering RNA (siRNA). The PICMs consisted of a poly(amidoamine) (PAMAM) dendrimer–nucleic acid core and a detachable poly(ethylene glycol)‐block‐poly( propyl methacrylate‐co‐methacrylic acid) (PEG‐b‐P(PrMA‐co‐MAA)) shell. The micelles displayed a mean hydrodynamic diameter ranging from 50 to 70 nm, a narrow size distribution, and a nearly neutral surface charge. They could be lyophilized without any additives and stored in dried form. Upon redispersion in water, no change in complexation efficiency or colloidal properties was observed. Entry of the micelles into cancers cells was mediated by a monoclonal antibody fragment positioned at the extremity of the PEG segment via a disulfide linkage. Upon cellular uptake and protonation of the MAA units in the acidic endosomal environment, the micelles lost their corona, thereby exposing their positively charged endosomolytic PAMAM/nucleic acid core. When these pH‐responsive targeted PICMs were loaded with AON or siRNAs that targeted the oncoprotein Bcl‐2, they exhibited a greater transfection activity than nontargeted PICMs or commercial PAMAM dendrimers. Moreover, their nonspecific cytotoxicity was lower than that of PAMAM. The pH‐responsive PICMs reported here appear as promising carriers for the delivery of nucleic acids.     

Theranostic USPIO‐Loaded Microbubbles for Mediating and Monitoring Blood‐Brain Barrier Permeation

Efficient and safe drug delivery across the blood‐brain barrier (BBB) remains one of the major challenges of biomedical and (nano‐) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)‐based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles within their shell, can be used to mediate and monitor BBB permeation. Upon exposure to transcranial ultrasound pulses, USPIO‐MB are destroyed, resulting in acoustic forces inducing vessel permeability. At the same time, USPIO are released from the MB shell, they extravasate across the permeabilized BBB and they accumulate in extravascular brain tissue, thereby providing non‐invasive R ₂*‐based magnetic resonance imaging information on the extent of BBB opening. Quantitative changes in R ₂* relaxometry are in good agreement with 2D and 3D microscopy results on the extravascular deposition of the macromolecular model drug fluorescein isothiocyanate (FITC)‐dextran into the brain. Such theranostic materials and methods are considered to be useful for mediating and monitoring drug delivery across the BBB and for enabling safe and efficient treatment of CNS disorders.     

A Conditionally Releasable “Do not Eat Me” CD47 Signal Facilitates Microglia‐Targeted Drug Delivery for the Treatment of Alzheimer's Disease

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.     

In vivo Imaging and Drug Storage by Quantum‐Dot‐Conjugated Carbon Nanotubes

A specially designed carbon nanotube (CNT) is developed for use in the early detection and treatment of cancer. The key functionalities for biomedical diagnosis and drug delivery are incorporated into the CNTs. In vivo imaging of live mice is achieved by intravenously injecting quantum dot (QD)‐conjugated CNT for the first time. With near infrared emission around 752 nm, the CNT with surface‐conjugated QD (CNT‐QD) exhibit a strong luminescence for non‐invasive optical in vivo imaging. CNT surface modification is achieved by a plasma polymerization approach that deposited ultra‐thin acrylic acid or poly(lactic‐co‐glycolic acid) (PLGA) films (∼3 nm) onto the nanotubes. The anticancer agent paclitaxel is loaded at 112.5 ± 5.8 µg mg⁻¹ to PLGA‐coated CNT. Cytotoxicity of this novel drug delivery system is evaluated in vitro using PC‐3MM2 human prostate carcinoma cells and quantified by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The in vivo distribution determined by inductively coupled plasma mass spectrometry (ICP‐MS) indicates CNT‐QD uptake in various organs of live animals.     

Time Controlled Protein Release from Layer‐by‐Layer Assembled Multilayer Functionalized Agarose Hydrogels

Axons of the adult central nervous system exhibit an extremely limited ability to regenerate after spinal cord injury. Experimentally generated patterns of axon growth are typically disorganized and randomly oriented. Support of linear axonal growth into spinal cord lesion sites has been demonstrated using arrays of uniaxial channels, templated with agarose hydrogel, and containing genetically engineered cells that secrete brain‐derived neurotrophic factor (BDNF). However, immobilizing neurotrophic factors secreting cells within a scaffold is relatively cumbersome, and alternative strategies are needed to provide sustained release of BDNF from templated agarose scaffolds. Existing methods of loading the drug or protein into hydrogels cannot provide sustained release from templated agarose hydrogels. Alternatively, here it is shown that pH‐responsive H‐bonded poly(ethylene glycol)(PEG)/poly(acrylic acid)(PAA)/protein hybrid layer‐by‐layer (LbL) thin films, when prepared over agarose, provided sustained release of protein under physiological conditions for more than four weeks. Lysozyme, a protein similar in size and isoelectric point to BDNF, is released from the multilayers on the agarose and is biologically active during the earlier time points, with decreasing activity at later time points. This is the first demonstration of month‐long sustained protein release from an agarose hydrogel, whereby the drug/protein is loaded separately from the agarose hydrogel fabrication process.     

Temperature‐Induced Hydrogels Through Self‐Assembly of Cholesterol‐Substituted Star PEG‐b‐PLLA Copolymers: An Injectable Scaffold for Tissue Engineering

Partially cholesterol‐substituted 8‐arm poly(ethylene glycol)‐block‐poly(L ‐lactide) (8‐arm PEG‐b‐PLLA‐cholesterol) has been prepared as a novel star‐shaped, biodegradable copolymer derivative. The amphiphilic 8‐arm PEG‐b‐PLLA‐cholesterol aqueous solution (polymer concentration, above 3 wt%) exhibits instantaneous temperature‐induced gelation at 34 °C, but the virgin 8‐arm PEG‐b‐PLLA does not, irrespective of concentration. Moreover, an extracellular matrix (ECM)‐like micrometer‐scale network structure has been created with favorable porosity for three‐dimensional proliferation of cells inside the hydrogel. This network structure is mainly attributed to specific self‐assembly between cholesterol groups. The 10 and 20 wt% hydrogels are eroded gradually in phosphate buffered saline at 37 °C over the course of a month, and after that the gel becomes completely dissociated. Moreover, L929 cells encapsulated into the hydrogel are viable and proliferate three‐dimensionally inside the hydrogels. Thus, in‐vitro cell culture studies demonstrate that 8‐arm PEG‐b‐PLLA‐cholesterol is a promising candidate as a novel injectable cellular scaffold.     

Photoacoustic Imaging Guided Near‐Infrared Photothermal Therapy Using Highly Water‐Dispersible Single‐Walled Carbon Nanohorns as Theranostic Agents

The poly(maleic anhydride‐alt‐1‐octadecene‐poly(ethylene glycol)) (C₁₈PMH‐PEG) modified single‐walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as‐prepared SWNHs/C₁₈PMH‐PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C₁₈PMH‐PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C₁₈PMH‐PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses.     

Magnetic and Temperature‐Sensitive Release Gels from Supramolecular Polymers

Supramolecular gels consisting of trivalent polyisobutylene and bivalent poly(ethylene oxide) are generated. Strong hydrogen bonding interactions, affixed to the end‐group moieties of the respective polymers (binding constant K_assn = 10⁵ M ^–1), serve as molecular glue, leading to the formation of weak gels. Two different gels were prepared: one, with a short telechelic poly(ethylene glycol) (PEG) segment (gel A), and one with a longer PEG segment (number‐average molecular weight M_n = 2000 g mol^–1) (gel B). Both gels show a significant increase in viscosity upon mixing of the two polymeric components, with a lag time of several minutes, indicative of nucleation mechanisms as the formation principle. However, only gel A displays classical gel‐like behavior, with a loss modulus G′ larger than the storage modulus G″ after formation. Both gels display microphase‐separated behavior with a spacing between 4–5 nm as probed via small‐angle X‐ray scattering (SAXS) and transmission electron microscopy (TEM) measurements. The incorporation of magnetic nanoparticles (Fe₂O₃; radius r = 3.5 nm) is successfully achieved, generating new magnetic gels with strongly thermoresponsive properties, displaying a strong temperature‐dependent release profile of included dye molecules. Magnetic measurements indicate a superparamagnetic behavior of the incorporated nanoparticles, prospecting the application as magneto‐sensitive delivery gels for pharmaceutical purposes.     

Multifunctional Micelles for Cancer Cell Targeting,Distribution Imaging,and Anticancer Drug Delivery

Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery were prepared from an environmentally‐sensitive graft copolymer, poly(N‐isopropyl acrylamide‐co‐methacryl acid)‐g‐poly(D ,L ‐lactide) (P(NIPAAm‐co‐MAAc)‐g‐PLA), a diblock copolymer, methoxy poly(ethylene glycol)‐b‐poly(D ,L ‐lactide) (mPEG‐PLA) and two functionalized diblock copolymers, galactosamine‐PEG‐PLA (Gal‐PEG‐PLA) and fluorescein isothiocyanate‐PEG‐PLA (FITC‐PEG‐PLA). Anticancer drug, free base doxorubicin (Dox) was incorporated into the inner core of multifunctional micelles by dialysis. From the drug release study, a change in pH (from pH 7.4 to 5.0) deformed the structure of the inner core from that of aggregated P(NIPAAm‐co‐MAAc), causing the release of a significant quantity of doxorubicin (Dox) from multifunctional micelles. Multifunctional micelles target specific tumors by an asialoglycoprotein (HepG2 cells)‐Gal (multifunctional micelle) receptor‐mediated tumor targeting mechanism. This mechanism then causes intracellular pH changes which induce Dox release from multifunctional micelles and that micelles have strong effects on the viability of HepG2 cells and are abolished by galactose. Confocal laser scanning microscopy (CLSM) reveals a clear distribution of multifunctional micelles. With careful design and sophisticated manipulation, polymeric micelles can be widely used in cancer diagnosis, cancer targeting, and cancer therapy simultaneously.     

Solid Free‐Form Fabrication of Tissue‐Engineering Scaffolds with a Poly(lactic‐co‐glycolic acid) Grafted Hyaluronic Acid Conjugate Encapsulating an Intact Bone Morphogenetic Protein–2/Poly(ethylene glycol) Complex

Despite wide applications of bone morphogenetic protein–2 (BMP‐2), there are few methods to incorporate BPM‐2 within polymeric scaffolds while maintaining biological activity. Solid free‐form fabrication (SFF) of tissue‐engineering scaffold is successfully carried out with poly(lactic‐co‐glycolic acid) grafted hyaluronic acid (HA‐PLGA) encapsulating intact BMP‐2/poly(ethylene glycol) (PEG) complex. HA‐PLGA conjugate is synthesized in dimethyl sulfoxide (DMSO) by the conjugation reaction of adipic acid dihydrazide modified HA (HA‐ADH) and PLGA activated with N,N′‐dicyclohexylcarbodiimide (DCC) and N‐hydroxysuccinimide (NHS). BMP‐2 is complexed with PEG, which is encapsulated within the PLGA domain of the HA‐PLGA conjugate by SFF to prepare tissue‐engineering scaffolds. In vitro release tests confirm the sustained release of intact BMP‐2 from the scaffolds for up to a month. After confirmation of the enhanced osteoblast cell growth, and high gene‐expression levels of alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX) in the cells, the HA‐PLGA/PEG/BMP‐2 scaffolds are implanted into calvarial bone defects of Sprague Dawley (SD) rats. Microcomputed tomography (μCT) and histological analyses with Masson's trichrome, and hematoxylin and eosin (H&E) staining reveal effective bone regeneration on the scaffolds of HA‐PLGA/PEG/BMP‐2 blends.     

A Hollow‐Core,Magnetic, and Mesoporous Double‐Shell Nanostructure: In Situ Decomposition/Reduction Synthesis,Bioimaging, and Drug‐Delivery Properties

A novel in situ decomposition/reduction approach is developed to manu­facture hollow core, magnetic, and mesoporous double‐shell nanostructures (HMMNSs) via in situ decomposition and reduction of a β‐FeOOH nanorod core and organosilicate‐incorporated silica‐shell precursor. The formed HMMNSs are then aminated by silanization for further covalent conjugation to rhodamine B isothiocyanate (RBITC) and poly(ethylene glycol) (PEG) chains. The resultant RBITC‐grafted and PEGylated nanocomposites (HMMNS–R/Ps) have excellent blood compatibility and very low cytotoxicity towards HeLa and MCF‐7 cells, and can be taken up by cancer cells effectively in a dose‐dependent manner, as confirmed by in vitro flow cytometry, confocal luminescence imaging, and magnetic resonance imaging (MRI) studies. In vivo MRI studies coupled with Prussian blue staining of slides from different organs show that the nanocomposites preferentially accumulate in liver and spleen after intravenous injection, which suggests a potential application of the nanocomposites as MRI contrast agents. Importantly, the HMMNS–R/P nanocomposites show high loading capacity for water‐insoluble anticancer drugs (docetaxel or camptothecin) owing to the presence of a large inner cavity and enhanced surface area and pore volume. Furthermore, the drug‐loaded nanocomposites exhibit greater cytotoxicity than the corresponding free drugs. These results confirm that the HMMNS–R/P nanocomposites are promising candidates for simultaneous bioimaging and drug delivery.     

Protein‐Release Behavior of Self‐Assembled PEG–β‐Cyclodextrin/PEG–Cholesterol Hydrogels

This paper reports on the degradation and protein release behavior of a self‐assembled hydrogel system composed of β‐cyclodextrin‐ (βCD) and cholesterol‐derivatized 8‐arm star‐shaped poly(ethylene glycol) (PEG₈). By mixing βCD‐ and cholesterol‐derivatized PEG₈ (molecular weights 10, 20 and 40 kDa) in aqueous solution, hydrogels with different rheological properties are formed. It is shown that hydrogel degradation is mainly the result of surface erosion, which depends on the network swelling stresses and initial crosslink density of the gels. This degradation mechanism, which is hardly observed for other water‐absorbing polymer networks, leads to a quantitative and nearly zero‐order release of entrapped proteins. This system therefore offers great potential for protein delivery.     

Matrix Metalloproteinase Responsive,Proximity‐Activated Polymeric Nanoparticles for siRNA Delivery

Small interfering RNA (siRNA) has significant potential to evolve into a new class of pharmaceutical inhibitors, but technologies that enable robust, tissue‐specific intracellular delivery must be developed before effective clinical translation can be achieved. A pH‐responsive, smart polymeric nanoparticle (SPN) with matrix metalloproteinase (MMP)‐7‐dependent proximity‐activated targeting (PAT) is described here. The PAT‐SPN is designed to trigger cellular uptake and cytosolic delivery of siRNA once activated by MMP‐7, an enzyme whose overexpression is a hallmark of cancer initiation and progression. The PAT‐SPN is composed of a corona‐forming polyethylene glycol (PEG) block, an MMP‐7‐cleavable peptide, a cationic siRNA‐condensing block, and a pH‐responsive, endosomolytic terpolymer block that drives self‐assembly and forms the PAT‐SPN core. With this novel design, the PEG corona shields cellular interactions until it is cleaved in MMP‐7‐rich environments, shifting the SPN ζ‐potential from +5.8 to +14.4 mV and triggering a 2.5 fold increase in carrier internalization. The PAT‐SPN exhibits pH‐dependent membrane disruptive behavior that enables siRNA escape from endo‐lysosomal pathways. Intracellular siRNA delivery and knockdown of the model enzyme luciferase in R221A‐Luc mammary tumor cells is significantly increased by MMP‐7 pre‐activation (p < 0.05). These combined data indicate that the PAT‐SPN provides a promising new platform for tissue‐specific, proximity‐activated siRNA delivery to MMP‐rich pathological environments.