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- Superstructured poly(amidoamine) dendrimer-based nanoconstructs as platforms for cancer nanomedicine: a concise reviewPublication . Song, Cong; Shen, Mingwu; Rodrigues, João; Mignani, Serge; Majoral, Jean-Pierre; Shi, XiangyangPoly(amidoamine) (PAMAM) dendrimers, as a family of synthetic macromolecules with highly branched interiors, abundant surface functional groups, and well-controlled architecture, have received immense scientific and technological interests for a range of biomedical applications, in particular cancer nanome dicine. However, due to the drawbacks of single-generation dendrimers with a quite small size (e.g., gen eration 5 (G5) PAMAM dendrimer has a size of 5.4 nm) such as limited drug loading capacity, restricted tumor passive targeting based on enhanced permeability and retention effect, and lack of versatility to render them with stimuli-responsiveness, superstructured dendrimeric nanoconstructs (SDNs) have been designed to break through these obstacles in their applications in cancer nanomedicine. Here, we review the recent advances related to the creation of SDNs such as dendrimer dumbbells, core–shell tecto den drimers, dendrimer nanoclusters (NCs), dendrimer nanogels and dendrimer-templated hybrid NCs, and how these SDNs have been designed as nanoplatforms for different biomedical applications related to cancer nanomedicine including MR imaging, drug/gene delivery, combination therapy and theranostics. This review concisely describes the latest key developments in the field and also discusses the possible challenges and perspectives for translation applications.
- Recent therapeutic applications of the theranostic principle with dendrimers in oncologyPublication . Mignani, Serge; Rodrigues, João; Tomás, Helena; Caminade, Anne-marie; Laurent, Régis; Shi, Xiangyang; Majoral, Jean-PierreAt the intersection between treatment and diagnosis,nanoparticlestechnologiesarestronglyimpactingthe development of both therapeutic and diagnostic agents. Consequently, the development of novel modalities for concomitant noninvasive therapy and diagnostics known as theranostics as a single platform has gained significant interests. These multifunctional theranostic platforms include carbon-based nanomaterials (e.g., carbon nanotubes), drug conjugates, aliphatic polymers, micelles, vesicles, core-shell nanoparticles,microbubblesanddendrimersbearingdifferent contrastagentsanddrugs,suchascytotoxiccompoundsinthe oncology domain. Dendrimers emerged as a new class of highly tunable hyperbranched polymers, and have been developed as useful theranostic platforms. Magnetic resonance imaging, gamma scintigraphy, computed tomography and optical imaging are the main techniques developed with dendrimers in the theranostic domain in oncology. Different imaging agents have been used such as Gd(III), 19F, Fe2O3 (MRI), 76Br (PET), 111In, 88Y, 153Gd, 188Re, 131I (SPECT), 177Lu, gold (CT) and boronated groups, siliconnaphthalocyanines, dialkylcarbocyanines and QDs (optical imaging dyes).
- Engineered non-invasive functionalized dendrimer/dendron-entrapped/complexed gold nanoparticles as a novel class of theranostic (radio)pharmaceuticals in cancer therapyPublication . Mignani, Serge; Shi, Xiangyang; Ceña, Valentin; Rodrigues, João; Tomás, Helena; Majoral, Jean-PierreNanomedicine represents a very significant contribution in current cancer treatment; in addition to surgical intervention, radiation and chemotherapeutic agents that unfortunately also kill healthy cells, inducing highly deleterious and often life-threatening side effects in the patient. Of the numerous nanoparticles used against cancer, gold nanoparticles had been developed for therapeutic applications. Inter alia, a large variety of den drimers, i.e. soft artificial macromolecules, have turned up as non-viral functional nanocarriers for entrapping drugs, imaging agents, and targeting molecules. This review will provide insights into the design, synthesis, functionalization, and development in biomedicine of engineered functionalized hybrid dendrimer-tangled gold nanoparticles in the domain of cancer theranostic. Several aspects are highlighted and discussed such as 1) dendrimer-entrapped gold(0) hybrid nanoparticles for the targeted imaging and treatment of cancer cells, 2) dendrimer encapsulating gold(0) nanoparticles (Au DENPs) for the delivery of genes, 3) Au DENPs for drug delivery applications, 4) dendrimer encapsulating gold radioactive nanoparticles for radiotherapy, and 5) dendrimer/dendron-complexed gold(III) nanoparticles as technologies to take down cancer cells.
- Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise ReviewPublication . Sun, Huxiao; Zhan, Mengsi; Mignani, Serge; Shcharbin, Dzmitry; Majoral, Jean-Pierre; Rodrigues, João; Shi, Xiangyang; Shen, MingwuCurcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic effects for clinical applications. A variety of nanocarriers have been successfully developed to improve the water solubility, in vivo distribution, and pharmacokinetics of Cur, as well as to enhance the ability of Cur to polarize macrophages and relieve macrophage oxidative stress or anti-apoptosis, thus accelerating the therapeutic effects of Cur on inflammatory diseases. Herein, we review the design and development of diverse Cur nanoformulations in recent years and introduce the biomedical applications and potential therapeutic mechanisms of Cur nanoformulations in common inflammatory diseases, such as arthritis, neurodegenerative diseases, respiratory diseases, and ulcerative colitis, by regulating macrophage behaviors. Finally, the perspectives of the design and preparation of future nanocarriers aimed at efficiently exerting the biological activity of Cur are briefly discussed.
- Morpholino-functionalized phosphorus dendrimers for precision regenerative medicine: osteogenic differentiation of mesenchymal stem cellsPublication . Li, Aijun; Fan, Yu; Cao, Xueyan; Chen, Liang; Wang, Le; Alves, Carla S.; Mignani, Serge; Majoral, Jean Pierre; Tomás, Helena; Shi, XiangyangA novel bioactive macromolecule based on morpholino-functiona lized phosphorus dendrimers (generation 2, G2-Mor+ ) was devel oped for osteogenic differentiation of mesenchymal stem cells (MSCs). Interestingly, through in vitro tests, it was shown that G2- Mor+ dendrimer can strongly promote the transformation of MSCs into osteoblasts, which implies the potential application of phos phorus de medicine.
- Endocannabinoid Degradation Enzyme Inhibitors as Potential Antipsychotics: A Medicinal Chemistry PerspectivePublication . Mangiatordi, Giuseppe Felice; Cavalluzzi, Maria Maddalena; Delre, Pietro; Lamanna, Giuseppe; Lumuscio, Maria Cristina; Saviano, Michele; Majoral, Jean-Pierre; Mignani, Serge; Duranti, Andrea; Lentini, GiovanniThe endocannabinoid system (ECS) plays a very important role in numerous physiological and pharmacological processes, such as those related to the central nervous system (CNS), including learning, memory, emotional processing, as well pain control, inflammatory and immune response, and as a biomarker in certain psychiatric disorders. Unfortunately, the half-life of the natural ligands responsible for these effects is very short. This perspective describes the potential role of the inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), which are mainly responsible for the degradation of endogenous ligands in psychic disorders and related pathologies. The examination was carried out considering both the impact that the classical exogenous ligands such as ∆ 9 -tetrahydrocannabinol (THC) and (−)-trans-cannabidiol (CBD) have on the ECS and through an analysis focused on the possibility of predicting the potential toxicity of the inhibitors before they are subjected to clinical studies. In particular, cardiotoxicity (hERG liability), probably the worst early adverse reaction studied during clinical studies focused on acute toxicity, was predicted, and some of the most used and robust metrics available were considered to select which of the analyzed compounds could be repositioned as possible oral antipsychotics.
- Phosphorus dendron nanomicelles as a platform for combination anti-inflammatory and antioxidative therapy of acute lung injuryPublication . Li, Jin; Chen, Liang; Li, Changsheng; Fan, Yu; Zhan, Mengsi; Sun, Huxiao; Mignani, Serge; Majoral, Jean-Pierre; Shen, Mingwu; Shi, XiangyangRationale: Development of novel nanomedicines to inhibit pro-inflammatory cytokine expression and reactive oxygen species (ROS) generation for anti-inflammatory therapy of acute lung injury (ALI) remains challenging. Here, we present a new nanomedicine platform based on tyramine-bearing two dimethylphosphonate sodium salt (TBP)-modified amphiphilic phosphorus dendron (C11G3) nanomicelles encapsulated with antioxidant drug curcumin (Cur). Methods: C11G3-TBP dendrons were synthesized via divergent synthesis and self-assembled to generate nanomicelles in a water environment to load hydrophobic drug Cur. The created C11G3-TBP@Cur nanomicelles were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular ROS elimination, pro-inflammatory cytokine inhibition and alveolar macrophages M2 type repolarization in vitro, and evaluated to assay their anti-inflammatory and antioxidative therapy effects of ALI mice model through pro-inflammatory cytokine expression level in bronchoalveolar lavage fluid and lung tissue, histological analysis and micro-CT imaging detection of lung tissue injury in vivo. Results: The nanomicelles with rigid phosphorous dendron structure enable high-capacity and stable Cur loading. Very strikingly, the drug-free C11G3-TBP micelles exhibit excellent cytocompatibility and intrinsic anti-inflammatory activity through inhibition of nuclear transcription factor-kappa B, thus causing repolarization of alveolar macrophages from M1 type to anti-inflammatory M2 type. Taken together with the strong ROS scavenging property of the encapsulated Cur, the developed nanomicelles enable effective therapy of inflammatory alveolar macrophages in vitro and an ALI mouse model in vivo after atomization administration. Conclusion: The created phosphorus dendron nanomicelles can be developed as a general nanomedicine platform for combination anti-inflammatory and antioxidative therapy of inflammatory diseases.
- Exploration of biomedical dendrimer space based on in-vitro physicochemical parameters: key factor analysis (Part 1)Publication . Mignani, Serge; Rodrigues, João; Roy, René; Shi, Xiangyang; Ceña, Valentin; El Kazzouli, Saïd; Majoral, Jean-PierreDendrimers are highly branched, star-shaped macromolecules with nanometer-scale dimensions that can be readily modified with a range of functional groups, thus modifying their physicochemical and biological properties. In nanomedicine, dendrimers can be used as vectors for the targeted delivery strategy of a variety of biologically active agents or can be used as drug per se. In the future, it will be necessary to designate and develop 'safe' dendrimers, which is currently a crucial concern. Here, we analyze the key in vitro physicochemical parameters to be considered for preclinical evaluation of biomedical dendrimers.
- Exploration of biomedical dendrimer space based on in-vivo physicochemical parameters: key factor analysis (Part 2)Publication . Mignani, Serge; Rodrigues, João; Roy, René; Shi, Xiangyang; Ceña, Valentin; El Kazzouli, Saïd; Majoral, Jean-PierreIn nanomedicine, the widespread concern of nanoparticles in general, and dendrimers, in particular, is the analysis of key in-vivo physicochemical parameters to ensure the preclinical and clinical development of 'safe' bioactive nanomaterials. It is clear that for biomedical applications, biocompatible dendrimers, used as nanocarriers or active per se, should be devoid of toxicity and immunogenicity, and have adequate PK/PD behaviors (adequate exposure) in order to diffuse in different tissues. Functionalization of dendrimers has a dramatic effect on in-vivo physicochemical parameters. In this review, we highlighted key in-vivo physicochemical properties, based on data from biochemical, cellular and animal models, to provide biocompatible dendrimers. Up-to-date, only scarce studies have been described on this topic.
- Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: how far can they be simplified?Publication . Mignani, Serge; Rodrigues, João; Tomás, Helena; Jalal, Rachid; Singh, Parvinder Pal; Majoral, Jean-Pierre; Vishwakarma, Ram A.During the past decade, decreasing the attrition rate of drug development candidates reaching the market has become one of the major challenges in pharmaceutical research and drug development (R&D). To facilitate the decision-making process, and to increase the probability of rapidly finding and developing high-quality compounds, a variety of multiparametric guidelines, also known as rules and ligand efficiency (LE) metrics, have been developed. However, what are the 'best' descriptors and how far can we simplify these drug-likeness prediction tools in terms of the numerous, complex properties that they relate to?