ATP/pH Dual Responsive Nanoparticle with d-[des-Arg10 ]Kallidin Mediated Efficient In Vivo Targeting Drug Delivery.

Inflammation has been reported as one significant hallmark of breast cancer in relation to tumor development, metastasis, and invasion. The bradykinin receptor 1 (B1R) is highly expressed on inflammatory breast tumor cells thus providing a promising targeting site for tumor recognition and sufficient receptor mediated endocytosis. In this study, the authors evaluate the targeting efficiency of l-form and d-form [des-Arg10 ]kallidin both in vitro and in vivo. To further improve the drug delivery efficiency, the authors establish a dandelion like nanoparticle by combining the polymeric drug conjugates and aptamer complex together. The doxorubicin conjugated polymer is complexed with adenosine-5'-triphosphate (ATP) sensitive hybridized aptamer in self-assembly process by intercalating into the double strand scaffolds. The acid labile conjugating bond and ATP sensitive aptamer endow the nanoparticle with dual responsiveness to intracellular milieu, thus triggering a quick drug release in tumor cells. Remarkable therapeutic effects and tuned in vivo pharmacokinetics profiles are shown by the aptamer complexed drug conjugates nanoparticle with B1R active targeting modification. Therefore the strategies of B1R targeting and ATP/pH dual-responsiveness nanoparticle help achieve enhanced drug accumulation within tumor cells and efficient chemotherapy for breast cancer.

Tumor-Targeting Micelles Based on Linear-Dendritic PEG-PTX8 Conjugate for Triple Negative Breast Cancer Therapy.

Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear-dendritic polymer-drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear-dendritic PEG-PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG-PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR-PEG-PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO-PEG-PTX8/PTX micelles. Furthermore, iNGR-PEG-PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.

Glycosaminoglycans' Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials.

Glycosaminoglycans (GAGs) are important for the occurrence of signaling molecules and maintenance of microenvironment within the extracellular matrix (ECM) in living tissues. GAGs and GAG-based biomaterial approaches have been widely explored to promote in situ tissue regeneration and repair by regulating the wound microenvironment, accelerating re-epithelialization, and controlling ECM remodeling. However, most approaches remain unacceptable for clinical applications. To improve insights into material design and clinical translational applications, this review highlights the innate roles and bioactive mechanisms of native GAGs during in situ wound healing and presents common GAG-based biomaterials and the adaptability of application scenarios in facilitating wound healing. Furthermore, challenges before the widespread commercialization of GAG-based biomaterials are shared, to ensure that future designed and constructed GAG-based artificial biomaterials are more likely to recapitulate the unique and tissue-specific profile of native GAG expression in human tissues. This review provides a more explicit and clear selection guide for researchers designing biomimetic materials, which will resemble or exceed their natural counterparts in certain functions, thereby suiting for specific environments or therapeutic goals.

Roles of Streptococcus mutans-Candida albicans interaction in early childhood caries: a literature review.

As one of the most common oral diseases in kids, early childhood caries affects the health of children throughout the world. Clinical investigations show the copresence of Candida albicans and Streptococcus mutans in ECC lesions, and mechanistic studies reveal co-existence of C. albicans and S. mutans affects both of their cariogenicity. Clearly a comprehensive understanding of the interkingdom interaction between these two microorganisms has important implications for ECC treatment and prevention. To this end, this review summarizes advances in our understanding of the virulence of both C. albicans and S. mutans. More importantly, the synergistic and antagonistic interactions between these two microbes are discussed.

Biomaterials releasing drug responsively to promote wound healing via regulation of pathological microenvironment.

Wound healing is characterized by complex, orchestrated, spatiotemporal dynamic processes. Recent findings demonstrated suitable local microenvironments were necessities for wound healing. Wound microenvironments include various biological, biochemical and physical factors, which are produced and regulated by endogenous biomediators, exogenous drugs, and external environment. Successful drug delivery to wound is complicated, and need to overcome the destroyed blood supply, persistent inflammation and enzymes, spatiotemporal requirements of special supplements, and easy deactivation of drugs. Triggered by various factors from wound microenvironment itself or external elements, stimuli-responsive biomaterials have tremendous advantages of precise drug delivery and release. Here, we discuss recent advances of stimuli-responsive biomaterials to regulate local microenvironments during wound healing, emphasizing on the design and application of different biomaterials which respond to wound biological/biochemical microenvironments (ROS, pH, enzymes, glucose and glutathione), physical microenvironments (mechanical force, temperature, light, ultrasound, magnetic and electric field), and the combination modes. Moreover, several novel promising drug carriers (microbiota, metal-organic frameworks and microneedles) are also discussed.

A bipolar membrane-based cation electrolytic membrane suppressor for ion chromatography.

A bipolar membrane (BPM)-based cation electrolytic membrane suppressor (CEMS) for ion chromatography is described. It has a sandwiched configuration, similar to that of commercial CEMS, except that a BPM and an anion exchange membrane (AEM) are respectively used to isolate the central eluent channel from two outer regenerant chambers. The AEM side of BPM is facing the central channel, contactless with the cathode. The suppression hydroxide ions are generated by enhanced water splitting at the junction layer of BPM. The suppressor showed comparable performance to common one in terms of suppressed background conductivity (∼0.38 µS/cm) and very low noise level (∼0.6 nS/cm). Possible electrochemically induced reductive deamination of AEM when immersed into the alkaline solution at the cathode can be avoided.

Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.

In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment.

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the 'don't eat me' signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel 'awakens' the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.

Reactive Oxygen Species-Biodegradable Gene Carrier for the Targeting Therapy of Breast Cancer.

An ideal gene-carrying vector is supposed to exhibit outstanding gene-condensing capability with positively charged macromolecules to protect the carried gene during in vivo circulation and a rapid dissociation upon microenvironmental stimuli at the aimed sites to release the escorted gene. Currently, it still remains a challenge to develop an ideal gene carrier with efficient transfection ability and low toxicity for clinical applications. Herein, we have innovatively introduced a reactive oxygen species (ROS)-biodegradable boric acid ester linkage in elaborating the design of a gene carrier. In virtue of the featured intracellular characteristics such as the high level of ROS in tumor cells, an ROS-biodegradable electropositive polymer derived from branched polyethylenimine (BPEI) with a low molecular weight (1.2k) through a cross-linking reaction by the boric acid ester bond was developed in this study to achieve condensation and escorting of carried genes. Furthermore, the polymer was modified with substance P (SP) peptide as the targeting ligand through polyethylene glycol. The final fabricated SP-cross-linked BPEI/plasmid DNA nanoparticles exhibit favorable biocompatibility, ROS-cleavability, and fine targeting ability as well as high transfection efficiency compared with parental BPEI1.2k both in vitro and in vivo. SP-cross-linked BPEI/small interfering RNA (pololike kinase 1) polyplex possesses favorable gene-silencing effects in vitro and satisfactory antitumor ability in vivo. Hopefully, this novel cross-linked electropositive polymer may serve well as a safe and efficient gene-delivery vehicle in the clinic.

A targeting theranostics nanomedicine as an alternative approach for hyperthermia perfusion.

Real-time monitoring drug-release is often regarded crucial in theranostics nanomedicine design, since it provides precise establishment of spatio-temporal activation of the drug-release in vitro and in vivo. A symmetrical self-immolative drug-dye conjugation (DDC) prodrug is developed in this study with disulfide bond as the trigger. The prodrug can be escorted by targeting PEG-PLGA micelles and hereby accumulated in the tumor by both active and passive targeting effect. Glutathione (GSH) with higher concentration in the tumor microenvironment can readily cleave the disulfide bond to initiate a subsequent decomposition of DDC, where the drug and dye can be released simultaneously in a strict one-to-one mode. Upon the disintegration, the "Turned-On" probe can emit near-infrared (NIR) fluorescence, with the aim of providing accurate and real-time information for the prodrugs' activation and biodistribution in vivo in a non-invasive way. Furthermore, the released dye can meanwhile act as a photothermic sensitizer, which can in-situ assist a deep penetration for the released drug in the tumor tissue with enhanced therapeutic efficiency. This "babysitting" strategy provides new reference for designing versatile theranostic nanomedicines for preclinical evaluations and an alternative approach for hyperthermia perfusion in clinic.

Dimeric Prodrug Self-Delivery Nanoparticles with Enhanced Drug Loading and Bioreduction Responsiveness for Targeted Cancer Therapy.

Efficient drug accumulation in tumor cells is essential for cancer therapy. Herein, we developed dimeric prodrug self-delivery nanoparticles (NPs) with enhanced drug loading and bioreduction responsiveness for triple negative breast cancer (TNBC) therapy. Specially designed camptothecin dimeric prodrug (CPTD) containing a disulfide bond was constructed to realize intracellular redox potential controlled drug release. Direct conjugation of hydrophobic CPTD to poly(ethylene glycol) PEG5000, a prodrug-based amphiphilic CPTD-PEG5000 co-polymer was synthesized, which could encapsulate parental CPTD prodrug spontaneously and form ultrastable NPs due to the highly analogous structure. Such dimeric prodrug self-delivery nanoparticles showed ultrahigh stability with critical micelle concentration as low as 0.75 µg/mL and remained intact during endocytosis. In addition, neurotensin (NT), a 13 amino acid ligand, was further modified on the nanoparticles for triple negative breast cancer (TNBC) targeting. Optimized NT-CPTD NPs showed improved pharmacokinetics profile and increased drug accumulation in TNBC lesions than free CPT, which largely reduced the systemic toxicity and presented an improved anticancer efficacy in vivo. In summary, with advantages of extremely high drug loading capacity, tumor microenvironmental redox responsiveness, and targeted TNBC accumulation, NT-CPTD NPs showed their potential for effective triple negative breast cancer therapy.

Brain-Targeted Polymers for Gene Delivery in the Treatment of Brain Diseases.

Gene therapies have become a promising strategy for treating neurological disorders, such as brain cancer and neurodegenerative diseases, with the help of molecular biology interpreting the underlying pathological mechanisms. Successful cellular manipulation against these diseases requires efficient delivery of nucleic acids into brain and further into specific neurons or cancer cells. Compared with viral vectors, non-viral polymeric carriers provide a safer and more flexible way of gene delivery, although suffering from significantly lower transfection efficiency. Researchers have been devoted to solving this defect, which is attributed to the multiple barriers existing for gene therapeutics in vivo, such as systemic degradation, blood-brain barrier, and endosome trapping. This review will be mainly focused on systemically administrated brain-targeted polymers developed so far, including PEI, dendrimers, and synthetic polymers with various functions. We will discuss in detail how they are designed to overcome these barriers and how they efficiently deliver therapeutic nucleic acids into targeted cells.

Cell microenvironment-controlled antitumor drug releasing-nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy.

In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.