Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane-Polyurea Hybrid Nanocarrier.

Integration of photosensitizers (PSs) within nanoscale delivery systems offers great potential for overcoming some of the "Achiles' heels" of photodynamic therapy (PDT). Herein, we have encapsulated a mitochondria-targeted coumarin PS into amphoteric polyurethane-polyurea hybrid nanocapsules (NCs) with the aim of developing novel nanoPDT agents. The synthesis of coumarin-loaded NCs involved the nanoemulsification of a suitable prepolymer in the presence of a PS without needing external surfactants, and the resulting small nanoparticles showed improved photostability compared with the free compound. Nanoencapsulation reduced dark cytotoxicity of the coumarin PS and significantly improved in vitro photoactivity with red light toward cancer cells, which resulted in higher phototherapeutic indexes compared to free PS. Importantly, this nanoformulation impaired tumoral growth of clinically relevant three-dimensional multicellular tumor spheroids. Mitochondrial photodamage along with reactive oxygen species (ROS) photogeneration was found to trigger autophagy and apoptotic cell death of cancer cells.

Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανß3-targeted polyurethane-polyurea nanoparticles.

Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three-fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles.

A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent.

Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the long-wavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.

Redox-responsive polyurethane-polyurea nanoparticles targeting to aortic endothelium and atherosclerosis.

Aortic endothelial cell dysfunction is an early trigger of atherosclerosis, the major cause of the cardiovascular disease (CVD). Nanomedicines targeting vascular endothelium and lesions hold great promise as therapeutic solutions to vascular disorders. This study investigates the vascular delivery efficacy of polyurethane-polyurea nanocapsules (Puua-NCs) with pH-synchronized shell cationization and redox-triggered release. Fluorescent lipophilic dye DiI was encapsulated into Puua-NCs of variable sizes and concentrations. In vitro cellular uptake studies with human aortic endothelial cells showed that these Puua-NCs were taken up by cells in a dose-dependent manner. In apolipoprotein E-deficient mice fed a Western diet, a model of atherosclerosis, circulating Puua-NCs were stable and accumulated in aortic endothelium and lesions within 24 hours after intravenous administration. Treatment with thiol-reducing and oxidizing reagents disrupted the disulfide bonds on the surface of internalized NCs, triggering disassembly and intracellular cargo release. Ultimately, Puua-NCs are a potential redox-controllable cardiovascular drug delivery system.

Novel Tumor-Targeted Self-Nanostructured and Compartmentalized Water-in-Oil-in-Water Polyurethane-Polyurea Nanocapsules for Cancer Theragnosis.

Encapsulation of water-soluble bioactive compounds for enabling specific accumulation in tumor locations, while avoiding premature clearance and/or degradation in the bloodstream, is one of the main hallmarks in nanomedicine, especially that of NIR fluorescent probes for cancer theragnosis. The herein reported technology furnishes water-dispersible double-walled polyurethane-polyurea hybrid nanocapsules (NCs) loaded with indocyanine green (ICG-NCs), using a versatile and highly efficient one-pot and industrially scalable synthetic process based on the use of two different prepolymers to set up the NCs walls. Flow cytometry and confocal microscopy confirmed that both ICG-loaded NCs internalized in monocyte-derived dendritic cells (moDCs). The in vivo analysis of xenograft A375 mouse melanoma model revealed that amphoteric functionalization of NCs' surface promotes the selective accumulation of ICG-NCs in tumor tissues, making them promising agents for a less-invasive theragnosis of cancer.

Multi-Smart and Scalable Bioligands-Free Nanomedical Platform for Intratumorally Targeted Tambjamine Delivery, a Difficult to Administrate Highly Cytotoxic Drug.

Cancer is one of the leading causes of mortality worldwide due, in part, to limited success of some current therapeutic approaches. The clinical potential of many promising drugs is restricted by their systemic toxicity and lack of selectivity towards cancer cells, leading to insufficient drug concentration at the tumor site. To overcome these hurdles, we developed a novel drug delivery system based on polyurea/polyurethane nanocapsules (NCs) showing pH-synchronized amphoteric properties that facilitate their accumulation and selectivity into acidic tissues, such as tumor microenvironment. We have demonstrated that the anticancer drug used in this study, a hydrophobic anionophore named T21, increases its cytotoxic activity in acidic conditions when nanoencapsulated, which correlates with a more efficient cellular internalization. A biodistribution assay performed in mice has shown that the NCs are able to reach the tumor and the observed systemic toxicity of the free drug is significantly reduced in vivo when nanoencapsulated. Additionally, T21 antitumor activity is preserved, accompanied by tumor mass reduction compared to control mice. Altogether, this work shows these NCs as a potential drug delivery system able to reach the tumor microenvironment, reducing the undesired systemic toxic effects. Moreover, these nanosystems are prepared under scalable methodologies and straightforward process, and provide tumor selectivity through a smart mechanism independent of targeting ligands.

On the Importance of Polyurethane and Polyurea Nanosystems for Future Drug Delivery.

BACKGROUND: During the last decade, polyurethanes and polyureas have emerged as promising alternatives to classical polyacrylate-, polyester- and polyaminoacid-based drug delivery nanosystems. They are not only biocompatible and biodegradable, but also facilitate the manufacture of polymeric nanostructured nanoparticles in quantitative yields. The versatile chemistry reduces the amount of organic solvents used and allows the straightforward multifunctionalization of polymer precursors with the desired targeting molecule at each stage of the process. OBJECTIVES: To highlight the common issues encountered in current drug delivery systems (DDSs) and the state of the art of polyurethane and polyurea polymers that self-assemble in a stratified manner by hydrophobic interactions. Finally, we discuss the importance of taking a holistic view when applying polymer nanotechnologies, in order to enhance their efficiency during preclinical and clinical studies. CONCLUSIONS: Polyurethane-polyurea nanoparticles (PUUa NPs) emerge as suitable platforms to be manufactured in a cost-effective manner at industrial scale and following environmentally friendly synthetic methods. Furthermore, they allow the controlled delivery of a wide range of drugs and can be rapidly adapted to many clinical requirements by means of FDA-approved precursors. Additionally, the ease with which PUUa nanoparticles are biodegraded ensures control over temporal aspects of drug delivery compared to other nanosystems. These advantages make PUUa NPs attractive drug delivery vehicles as long as adequate safety and ethical guidelines for new NP formulations are developed.

Nanoencapsulated budesonide in self-stratified polyurethane-polyurea nanoparticles is highly effective in inducing human tolerogenic dendritic cells.

The design of innovative strategies to selectively target cells, such antigen-presenting cells and dendritic cells, in vivo to induce immune tolerance is gaining interest and relevance for the treatment of immune-mediated diseases. A novel loaded-nanosystem strategy to generate tolerogenic dendritic cells (tol-DCs) was evaluated. Hence budesonide (BDS) was encapsulated in multiwalled polyurethane-polyurea nanoparticles (PUUa NPs-BDS) based on self-stratified polymers by hydrophobic interactions at the oil-water interface. DCs treated with encapsulated BDS presented a prominent downregulation of costimulatory molecules (CD80, CD83 and MHCII) and upregulation of inhibitory receptors. Moreover, DCs treated with these PUUa NPs-BDS also secreted large amounts of IL-10, a crucial anti-inflammatory cytokine to induce tolerance, and inhibited T lymphocyte activation in a specific manner compared to those cells generated with free BDS. These results demonstrate that PUUa NPs-BDS are a highly specific and efficient system through which to induce DCs with a tolerogenic profile. Given the capacity of PUUa NPs-BDS, this delivery system has a clear advantage for translation to in vivo studies.

Multifunctionalized polyurethane-polyurea nanoparticles: hydrophobically driven self-stratification at the o/w interface modulates encapsulation stability.

Polyurethane-polyurea (PUUa) reactive prepolymers with adjusted hydrophobic and hydrophilic dangling chains to achieve multiwalled sub-30 nm nanoparticles are presented. The combination of an amphiphilic and a hydrophobic prepolymer at the oil-water interface creates a stratified shell by hydrophobic interactions. These novel nanostructures enhance the encapsulation stability of lipophilic compounds compared to monowalled nanostructures and facilitate the selective and ordered functionalization along the multiwalled shell with bioactive motifs. As proof of concept, PUUa nanoparticles have been engineered with disulfide bonds and an αvß3 integrin-selective cyclic RGD peptide (cRGDfK) providing our system with glutathione (GSH) triggered controlled release and cell targeting specificity to U87 tumor cells.

Correction: Multifunctionalized polyurethane-polyurea nanoparticles: hydrophobically driven self-stratification at the o/w interface modulates encapsulation stability.

Correction for 'Multifunctionalized polyurethane-polyurea nanoparticles: hydrophobically driven self-stratification at the o/w interface modulates encapsulation stability' by Pau Rocas et al., J. Mater. Chem. B, 2015, DOI: .

Installing multifunctionality on titanium with RGD-decorated polyurethane-polyurea roxithromycin loaded nanoparticles: toward new osseointegrative therapies.

A novel class of polyurethane-polyurea nanoparticles (PUUa NPs) to install multifunctionality on biomaterials is presented. Biofunctionalization of titanium with roxithromycin loaded RGD-decorated PUUa NPs results in an outstanding improvement of osteoblast adhesion and strong suppression of bacterial attachment. This strategy represents a powerful approach to enhance the osseointegration of implant materials.