An injectable and biodegradable zwitterionic gel for extending the longevity and performance of insulin infusion catheters.

Continuous subcutaneous insulin infusion (CSII) is an essential insulin replacement therapy in the management of diabetes. However, the longevity of clinical CSII is limited by skin complications, by impaired insulin absorption and by occlusions associated with the subcutaneous insertion of CSII catheters, which require replacement and rotation of the insertion site every few days. Here we show that a biodegradable zwitterionic gel covering the tip end of commercial off-the-shelf CSII catheters fully resolves early skin irritations, extends the longevity of catheters and improves the rate of insulin absorption (also with respect to conventional syringe-based subcutaneous injection) for longer than 6 months in diabetic mice, and by 11 days in diabetic minipigs (from 2 to 13 days, under standard CSII-wearing conditions of insulin pump therapy and in a continuous basal-plus-bolus-infusion setting). The implanted gel displayed anti-inflammatory and anti-foreign-body-reaction properties and promoted the local formation of new blood vessels. The gel is subcutaneously injected before the tip of catheter is inserted into it, and should be generally applicable to CSII catheters and other implantable devices.

ROS-Responsive Nanoparticle Delivery of mRNA and Photosensitizer for Combinatorial Cancer Therapy.

Messenger RNA (mRNA) therapy has shown tremendous potential for different diseases including cancer. While mRNA has been extensively used in cancer vaccine development as antigen or in cancer immunotherapy as immunomodulatory agent, the combination of mRNA therapy with photodynamic therapy has not been explored in cancer treatment. Herein, we report a reactive oxygen species (ROS)-responsive polymeric nanoparticle (NP) platform for first-in-field codelivery of mRNA and photosensitizer for effective cancer treatment. We developed ROS-responsive oligomer-based polymeric NPs and applied them to test a combination of p53 mRNA and indocyanine green (ICG). The ROS-triggered disassembly of the NPs could promote mRNA translation efficiency, whereby p53 expression induced apoptosis of lung tumor cells. Meanwhile, the released ICG could lead to generation of ROS under 808 nm laser irradiation to induce photodynamic therapy. The NP codelivery of p53 mRNA and ICG demonstrated an effective and safe anti-tumor effect in a lung cancer model.

Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy.

Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.

Biodegradable Zwitterionic Cream Gel for Effective Prevention of Postoperative Adhesion.

Postoperative peritoneal adhesions were frequent complications for almost any types of abdominal and pelvic surgery. This led to numerous medical problems and huge financial burden to the patients. Current anti-adhesion strategies focused mostly on physical barriers including films and hydrogels. However, they can only alleviate or reduce adhesions to certain level and their applying processes were far from ideal. This work reported the development of a biodegradable zwitterionic cream gel presenting a series of characters for an idea anti-adhesion material, including unique injectable yet malleable and self-supporting properties, which enabled an instant topical application, no curing, waiting or suturing, no hemostasis requirement, protein/cell resistance and biodegradability. The cream gel showed a major advancement in anti-adhesion efficacy by completely and reliably preventing a primary and a more severe recurrent adhesion in rat models.

Fouling-resistant zwitterionic polymers for complete prevention of postoperative adhesion.

Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the "nonfouling" zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our "complete prevention" approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.

Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions.

Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.

Engineering and Application Perspectives on Designing an Antimicrobial Surface.

Infections, contaminations, and biofouling resulting from micro- and/or macro-organisms remained a prominent threat to the public health, food industry, and aqua-/marine-related applications. Considering environmental and drug resistance concerns as well as insufficient efficacy on biofilms associated with conventional disinfecting reagents, developing an antimicrobial surface potentially improved antimicrobial performance by directly working on the microbes surrounding the surface area. Here we provide an engineering perspective on the logic of choosing materials and strategies for designing antimicrobial surfaces, as well as an application perspective on their potential impacts. In particular, we analyze and discuss requirements and expectations for specific applications and provide insights on potential misconnection between the antimicrobial solution and its targeted applications. Given the high translational barrier for antimicrobial surfaces, future research would benefit from a comprehensive understanding of working mechanisms for potential materials/strategies, and challenges/requirements for a targeted application.

Biomaterial-tight junction interaction and potential impacts.

The active pharmaceutical ingredients (APIs) have to cross the natural barriers and get into the blood to impart the pharmacological effects. The tight junctions (TJs) between the epithelial cells serve as the major selectively permeable barriers and control the paracellular transport of the majority of hydrophilic drugs, in particular, peptides and proteins. TJs perfectly balance the targeted transport and the exclusion of other unexpected pathogens under the normal conditions. Many biomaterials have shown the capability to open the TJs and improve the oral bioavailability and targeting efficacy of the APIs. Nevertheless, there is limited understanding of the biomaterial-TJ interactions. The opening of the TJs further poses the risk of autoimmune diseases and infections. This review article summarizes the most updated literature and presents insights into the TJ structure, the biomaterial-TJ interaction mechanism, the benefits and drawbacks of TJ disruption, and methods for evaluating such interactions.

Hydrophobic drug self-delivery systems as a versatile nanoplatform for cancer therapy: A review.

Drug self-delivery systems exactly present nanoscale characteristics without the support of any external carrier materials, have been rapidly developed because of low-cost preparation, excellent and fixed drug loading capacity, no need for carrier synthesis and no carrier-induced toxicity and immunogenicity. In general, amphipathy is indispensable for such design, for the amphiphilic drug conjugates could spontaneously self-assemble into nano-sized architectures above a critical concentration. Nevertheless, some elaborate designs on bonds and specified conjugates with no amphipathy anymore appeared in recent years, which create a novel and broad platform for the fabrication of hydrophobic drug self-delivery systems (HDSDSs), involving lipid-drug conjugates, drug-drug conjugates, and fluorescent dye -drug conjugates. In this review, we present the major types of HDSDSs and expound their self-assembly mechanism and fabrication strategies. And we emphatically discuss some representative achievements of these different types of HDSDSs for monotherapy, combinational therapy and theranostics in the aspect of cancer therapy. In addition, we discuss the future prospects of such kind of nanomedicine, which hold a span-new direction for cancer therapy on account of the excellent drug behavior in vitro and in vivo and the great potential to standardize the commercial production.

Paclitaxel-Paclitaxel Prodrug Nanoassembly as a Versatile Nanoplatform for Combinational Cancer Therapy.

Recently, nanomedicine without drug carriers has attracted many pharmacists' attention. A novel paclitaxel-s-s-paclitaxel (PTX-s-s-PTX) conjugate with high drug loading (∼78%, w/w) was synthesized by conjugating paclitaxel to paclitaxel by using disulfide linkage. The conjugate could self-assemble into uniform nanoparticles (NPs) with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) encapsulated within the core of PTX-s-s-PTX NPs for photothermal therapy (PTT). The DiR-loaded self-assembled nanoparticles (DSNs) had a mean diameter of about 150 nm and high stability in biological condition. A disulfide bond is utilized as a redox-responsive linkage to facilitate a rapid release of paclitaxel in tumor cells. DSNs indicated significant cytotoxicity as a result of the synergetic chemo-thermal therapy. DSNs were featured with excellent advantages, including high drug loading, redox-responsive releasing behavior of paclitaxel, capability of loading with photothermal agents, and combinational therapy with PTT. In such a potent nanosystem, prodrug and photothermal strategy are integrated into one system to facilitate the therapy efficiency.

Redox-Sensitive Citronellol-Cabazitaxel Conjugate: Maintained in Vitro Cytotoxicity and Self-Assembled as Multifunctional Nanomedicine.

Citronellol-cabazitaxel (CIT-ss-CTX) conjugate self-assembled nanoparticles (CSNPs) were designed and prepared by conjugating cabazitaxel with citronellol via the disulfide bond that is redox-sensitive to the high concentration of glutathione within tumor cells. Notably, the CSNPs maintained in the cell cytotoxicity. Moreover, the AUC0-t of CSNPs was 6.5-fold higher than that of cabazitaxel solutions and the t1/2 was prolonged 2.3 times. Furthermore, we found that CSNPs could be employed as an efficient carrier for other hydrophobic drugs or imaging agents. Thus, the in vivo targeting study was implemented via using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR)-loaded CSNPs as imaging agent, which showed CSNPs could effectively accumulate at the tumor site. Curcumin, a hydrophobic anticancer drug, was successfully loaded in CSNPs which exhibits good stability and synergistic antitumor effects. The citronellol-cabazitaxel conjugate therefore has a promising perspective as a multifunctional nanomedicine for combination therapy and theranostics attributed to its long-circulation property, redox-sensitive mechanism, and high drug coloading capability.

Preparation, characterization and in vivo evaluation of amorphous tacrolimus nanosuspensions produced using CO2-assisted in situ nanoamorphization method.

Unlike conventional 'top-down' and 'bottom-up' techniques, a novel low-cost CO2-assisted in situ nanoamorphization (ISN) method has been developed to prepare amorphous drug nanosuspensions. In order to improve the dissolution rate and oral bioavailability of tacrolimus (FK506), herein FK506 nanosuspensions with different particle size were successfully prepared using ISN method through adjusting the amount of acid-base pair and the stabilizer, the mean particle sizes of obtained FK506 nanosuspensions were 167.3±2.8nm (FK506-NA), 302.8±2.0nm (FK506-NB) and 513.5±15.1nm (FK506-NC), respectively. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of FK506 in all nanosuspensions that would be beneficial to the improvement of drug bioavailability because the amorphous drug form is more soluble and has a higher dissolution rate than the crystalline state. In vitro dissolution studies showed that the dissolution rate order of different formulation is as follows: FK506-NB>FK506-NA>FK506-NC>FK506-D (without acid-base pair included)>Prograf(®) (commercial hard capsule). In vivo pharmacokinetic studies showed that all FK506 nanosuspensions clearly increased the oral bioavailability of FK506 in comparison with Prograf(®), especially for FK506-NB. The Cmax and AUC0-12h of FK506-NB were about 2.05-fold (p<0.01) and 1.5-fold (p<0.05) higher than that of Prograf(®). These findings suggest that this simple and versatile ISN technique has great potential for use in the preparation of nanosuspensions to increase drug oral bioavailability.

A new approach to produce drug nanosuspensions CO2-assisted effervescence to produce drug nanosuspensions.

The exploration of a simple and robust approach to produce nanosuspensions is a meaningful attempt for clinical translation. CO2-assisted effervescence was firstly developed to prepare nanosuspensions and was found to be easy for scale-up. Drug nanosuspensions were easily obtained by adding aqueous carbonate to the pre-treated mixture of drug, stabilizer and organic acid. The burst of CO2 bubbles resulted from the acid-base reaction insert a micro gas bubble smashing and mixing effect to the formation of nanosuspensions, leading to smaller sizes and a refined size distribution. We successfully prepared nanosuspensions with twelve structurally diverse drugs. Alternatively, solid carbonate blended with the mixture, allowing for later addition of water, also facilitates the formation of amorphous nanosuspensions. We defined this approach as in situ nanoamorphization (ISN). Intensive in vitro and in vivo investigations for itraconazole and cabazitaxel nanosuspensions validate the availability for administration.

Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus.

To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.