Design of effective nanomedicines to modulate multiple immune cells to overcome the immune‐suppressive tumor microenvironment is desirable to improve the overall poor clinical outcomes of ...immunotherapy. Herein, a nanomedicine platform is reported based on chemotherapeutic drug doxorubicin (DOX)‐loaded phosphorus dendron micelles (M‐G1‐TBPNa@DOX, TBP, tyramine bearing two dimethylphosphonate) with inherent immunomodulatory activity for synergistic tumor chemoimmunotherapy. The M‐G1‐TBPNa@DOX micelles with good stability and a mean particle size of 86.4 nm can deliver DOX to solid tumors to induce significant tumor cell apoptosis and immunogenic cell death (ICD). With the demonstrated intrinsic activity of M‐G1‐TBPNa that can promote the proliferation of natural killer (NK) cells, the ICD‐resulted maturation of dendritic cells of the DOX‐loaded micelles, and the combination of anti‐PD‐L1 antibody, the synergistic modulation of multiple immune cells through NK cell proliferation, recruitment of tumor‐infiltrating NK cells and cytotoxic T cells, and decrease of regulatory T cells for effective tumor chemoimmunotherapy with strong antitumor immunity and immune memory effect for effective prevention of lung metastasis are demonstrated. The developed phosphorous dendron micelles may hold great promise to be used as an advanced nanomedicine formulation for synergistic modulation of multiple immune cells through NK cell proliferation for effective chemoimmunotherapy of different tumor types.
A doxorubicin‐loaded nanomedicine formulation based on phosphorus dendron micelles with intrinsic immunomodulatory activity is constructed. The created nanomedicine can synergistically proliferate natural killer (NK) cells, recruit tumor‐infiltrating NK cells and cytotoxic T cells, and decrease regulatory T cells, thus allowing for chemoimmunotherapy of tumors with strong antitumor immunity and immune memory effect for effective prevention of lung metastasis.
Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long‐term antitumor immunity still remains to be an extreme challenge. Herein, the design of an advanced ...redox‐responsive nanomedicine formulation based on phosphorus dendrimer–copper(II) complexes (1G3‐Cu)‐ and toyocamycin (Toy)‐loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM) are reported. The designed GCT@CM NPs with a size of 210 nm are stable under physiological conditions but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co‐loading of 1G3‐Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3‐Cu‐induced mitochondrial dysfunction and Toy‐mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor‐infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3‐Cu render the GCT@CM NPs with homotypic targeting and T1‐weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP‐mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy‐potentiated immunotherapy of different tumor types through different mechanisms or synergies.
Redox‐responsive polymeric nanoparticles (NPs) co‐loaded with phosphorus dendrimer–copper(II) complexes and toyocamycin and camouflaged with cancer cell membranes are developed. The NPs can be dissociated in the tumor microenvironment to release drugs for efficient tumor chemotherapy through mitochondrial dysfunction and endoplasmic reticulum stress aggravation, which significantly potentiates tumor immunotherapy after combination with programmed cell death ligand 1 antibody to effectively inhibit tumor recurrence and metastasis.
Irresponsiveness of triple negative breast cancer (TNBC) toward conventional therapies has drawn attention toward siRNA therapeutics. In gene delivery, dendrimers are gaining significant attention ...due to their characteristic features and polo‐like kinase (PLK1) is reported as a potential target for TNBC. In this work, phosphorus and polyamidoamine dendrimer (generation 3 and 4 of each type) are explored to address delivery challenges of PLK1 siRNA (siPLK1). Dendriplexes were formed and complexation was found at 3:1 N/P ratio for all dendrimers by gel electrophoresis. Complexation was also supported by zeta potential, circular dichroism and intercalation assay. Dendriplexes were found to be stable in presence of ribonuclease and serum. Dendriplexes resulted in enhanced cell uptake of siPLK1 compared to siPLK1 solution in MDA‐MB‐231 and MCF‐7 cells. Dendriplexes caused increased cell arrest in sub‐G1 phase compared to solution. These observations suggested phosphorus and polyamidoamine dendrimers as potential carriers for siPLK1 delivery to treat TNBC.
There are several routes of administration to the brain, including intraparenchymal, intraventricular, and subarachnoid injections. The blood-brain barrier (BBB) impedes the permeation and access of ...most drugs to the central nervous system (CNS), and consequently, many neurological diseases remain undertreated. For past decades, to circumvent this effect, several nanocarriers have been developed to deliver drugs to the brain. Importantly, intranasal (IN) administration can allow direct delivery of drugs into the brain through the anatomical connection between the nasal cavity and brain without crossing the BBB. In this regard, dendrimers may possess great potential to deliver drugs to the brain by IN administration, bypassing the BBB and reducing systemic exposure and side effects, to treat diseases of the CNS. In this original concise review, we highlighted the few examples advocated regarding the use of dendrimers to deliver CNS drugs directly via IN. This review highlighed the few examples of the association of dendrimer encapsulating drugs (e.g., small compounds: haloperidol and paeonol; macromolecular compounds: dextran, insulin and calcitonin; and siRNA) using IN administration. Good efficiencies were observed. In addition, we will present the in vivo effects of PAMAM dendrimers after IN administration, globally, showing no general toxicity.
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•Nose to brain transport pathways.•Nasal route of administration for the treatment of acute and chronic conditions.•Dendrimer platforms as effective nanocarriers to brain.•Nose to brain transport pathways of drugs in association with dendrimers using intranasal administration route.•In vivo neurological effects of nasal exposure of dendrimers.
The application of nanotechnology in biological and medical fields have resulted in the creation of new devices, supramolecular systems, structures, complexes, and composites. Dendrimers are ...relatively new nanotechnological polymers with unique features; they are globular in shape, with a topological structure formed by monomeric subunit branches diverging to the sides from the central nucleus. This review analyzes the main features of dendrimers and their applications in biology and medicine regarding cancer treatment. Dendrimers have applications that include drug and gene carriers, antioxidant agents, imaging agents, and adjuvants, but importantly, dendrimers can create complex nanosized constructions that combine features such as drug/gene carriers and imaging agents. Dendrimer‐based nanosystems include different metals that enhance oxidative stress, polyethylene glycol to provide biosafety, an imaging agent (a fluorescent, radioactive, magnetic resonance imaging probe), a drug or/and nucleic acid that provides a single or dual action on cells or tissues. One of major benefit of dendrimers is their easy release from the body (in contrast to metal nanoparticles, fullerenes, and carbon nanotubes), allowing the creation of biosafe constructions. Some dendrimers are already clinically approved and are being used as drugs, but many nanocomplexes are currently being studied for clinical practice. In summary, dendrimers are very useful tool in the creation of complex nanoconstructions for personalized nanomedicine.
This article is categorized under:
Diagnostic Tools > Diagnostic Nanodevices
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Applications of dendrimer‐based complexes.
Drugs are introduced into the body by numerous routes such as enteral (oral, sublingual and rectum administration), parenteral (intravascular, intramuscular, subcutaneous and inhalation ...administration), or topical (skin and mucosal membranes). Each route has specific purposes, advantages and disadvantages. Today, the oral route remains the preferred one for different reasons such as ease and compliance by patients. Several nanoformulated drugs have been already approved by the FDA, such as Abelcet®, Doxil®, Abraxane® or Vivagel®(Starpharma) which is an anionic G4-poly(l-lysine)-type dendrimer showing potent topical vaginal microbicide activity. Numerous biochemical studies, as well as biological and pharmacological applications of both dendrimer based products (dendrimers as therapeutic compounds per se, like Vivagel®) and dendrimers as drug carriers (covalent conjugation or noncovalent encapsulation of drugs) were described. It is widely known that due to their outstanding physical and chemical properties, dendrimers afforded improvement of corresponding carried-drugs as dendrimer–drug complexes or conjugates (versus plain drug) such as biodistribution and pharmacokinetic behaviors. The purpose of this manuscript is to review the recent progresses of dendrimers as nanoscale drug delivery systems for the delivery of drugs using enteral, parenteral and topical routes. In particular, we focus our attention on the emerging and promising routes such as oral, transdermal, ocular and transmucosal routes using dendrimers as delivery systems.
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Two families of phosphorhydrazone dendrons having either an azide or an alkyne linked to the core and diverse types of pyridine derivatives as terminal functions have been synthesized and ...characterized. These dendrons were grafted via click reaction to graphene oxide (GO) functionalized with either alkyne or azide functions, respectively. The resulting modified‐GO and GO‐dendrons materials have been characterized by Fourier Transform Infrared (FTIR), Raman spectroscopy (RS), and Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses. In addition, the free dendrons and the dendrons grafted to GO were tested toward cancerous (HCT116) and non‐cancerous (RPE1) cell lines.
Several dendrons were functionalized on their surface by different types of pyridine‐imine functions, and at their core by either azide or alkyne. These dendrons were grafted to graphene oxide (GO) via “click” reactions between azide or alkyne at their core, and alkynes or azides on the surface of GO, respectively. The biological properties of these new materials were tested.
The development of a powerful nanoplatform to realize the simultaneous therapy and diagnosis of cancer using a similar element for theranostics remains a critical challenge. Herein, we report such a ...theranostic nanoplatform based on pyridine (Pyr)-functionalized generation 5 (G5) poly(amidoamine) dendrimers complexed with copper(II) (Cu(II)) for radiotherapy-enhanced T 1-weighted magnetic resonance (MR) imaging and the synergistic radio-chemotherapy of both tumors and tumor metastasis. In this study, amine-terminated G5 dendrimers were covalently linked with 2-pyridinecarboxylic acid, acetylated to neutralize their remaining terminal amines, and complexed with Cu(II) through both the internal tertiary amines and the surface Pyr groups to form the G5.NHAc-Pyr/Cu(II) complexes. We show that the complexes are able to inhibit the proliferation of different cancer cell lines with half-maximal inhibitory concentrations ranging from 4 to 10 μM and induce significant cancer cell apoptosis. Due to the presence of Cu(II), the G5.NHAc-Pyr/Cu(II) complexes display an r 1 relaxivity of 0.7024 mM–1 s–1, enabling effective in vivo MR imaging of tumor xenografts and lung metastatic nodules. Further, under radiotherapy (RT) conditions, the tumor MR imaging sensitivity can be significantly enhanced, and the G5.NHAc-Pyr/Cu(II) complexes enable the enhanced chemotherapy of both a xenografted tumor model and a blood-vessel metastasis model. With the demonstrated theranostic potential of the dendrimer-Cu(II) nanocomplexes without additional agents or elements for RT-enhanced MR imaging and chemotherapy of tumor and tumor metastasis, this novel Cu(II)-based nanohybrids may hold great promise for the theranostics of different cancer types and metastases.
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•The common forms of SDNs are concisely reviewed.•SDNs can be prepared using dendrimers as reactive modules via various methods.•The synthesized SDNs have varied sizes, dimensions, ...and dispersities.•SDNs enable improved cancer nanomedicine applications.•Perspectives related to SDNs applied in cancer nanomedicine have been discussed.
Poly(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 nanomedicine. However, due to the drawbacks of single-generation dendrimers with a quite small size (e.g., generation 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 dendrimers, 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.
Nanomedicine has emerged as a promising mean to improve theranostic efficacy and reduce side effects. Currently, only very small percentage of injected dose reaches the solid tumors after intravenous ...administration due to the systemic biological barriers, including blood circulation, reticuloendothelial system capture, vasculature extravasation, tissue accumulation, deep penetration, cellular internalization, lysosome escape, intracellular efflux, and cell nuclear targeting. To optimize clinical translation and exploitation of nanomedicine, we here propose three safe and effective strategies to systematically overcome all barriers by the novel design of smart and bioinspired systems for highly efficient theranostics of various diseases, such as cancers, neurodegenerations, myocardial infarctions, inflammations, and infections. (1) Surface charge conversion, (2) size transformation, (3) bioinspired systems display unprecedented potential to achieve higher requirement of precise and personalized medicine. Alone or specially together, these strategies can address different barriers with intrinsically conflicting and promote the development of successful disease theranostics, that is impossible for almost of conventional delivery systems. Moreover, the challenges and perspectives of next-generation smart nanomedicine are featured for accurate theranostics and clinical practice in various diseases.
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