Folic Acid-Decorated Polyamidoamine Dendrimer Exhibits High Tumor Uptake and Sustained Highly Localized Retention in Solid Tumors: Its Utility for Local siRNA Delivery
TL;DR: It is demonstrated that localized delivery of FR-targeted PAMAM dendrimer G4 complexed with siVEGFA resulted in pronounced tumor suppression in an HN12 xenograft tumor model.
About: This article is published in Acta Biomaterialia.The article was published on 2017-07-15 and is currently open access. It has received 47 citations till now. The article focuses on the topics: Head and neck squamous-cell carcinoma & Gene delivery.
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TL;DR: In this paper, a review of dendrimer-based targeted delivery of drugs/genes and co-delivery systems mainly for cancer therapy is presented, where the authors discuss dendriplexes that can preserve the nucleic acids from degradation.
250 citations
TL;DR: This review focuses on the recent developments on the application in PAMAM dendrimers as effective carriers for drug and gene delivery in cancer therapy, including: a) PAM AM for anticancer drug delivery; b) P AMAM and gene therapy; c) PPMAM used in overcoming tumor multidrug resistance; d) PamAM used for hybrid nanoparticles; and e)PAMAM linked or loaded in other nanoparticles.
192 citations
TL;DR: Folic acid (FA) is one of the biologic molecules which has been targeted overexpressed‐folic acid receptor (FR) on the surface of cancer cells and conjugation of FA to NPs most easily enhances the FR‐mediated targeting delivery of therapeutic agents.
Abstract: Conventional chemotherapeutic approaches in cancer therapy such as surgery, chemotherapy, and radiotherapy have several disadvantages due to their nontargeted distributions in the whole body. On the other hand, nanoparticles (NPs) based therapies are remarkably progressing to solve several limitations of conventional drug delivery systems (DDSs) including nonspecific biodistribution and targeting, poor water solubility, weak bioavailability and biodegradability, low pharmacokinetic properties, and so forth. The enhanced permeability and retention effect escape from P-glycoprotein trap in cancer cells as a passive targeting mechanism, and active targeting strategies are also other most important advantages of NPs in cancer diagnosis and therapy. Folic acid (FA) is one of the biologic molecules which has been targeted overexpressed-folic acid receptor (FR) on the surface of cancer cells. Therefore, conjugation of FA to NPs most easily enhances the FR-mediated targeting delivery of therapeutic agents. Here, the recent works in FA which have been decorated NPs-based DDSs are discussed and cancer therapy potency of these NPs in clinical trials are presented.
106 citations
TL;DR: The main aim of this study is representing the use of dendrimers as novel nanocarriers for phytochemical bioactive compounds to deal with solubility, stability, and bioavailability issues.
89 citations
TL;DR: A novel type of DOX and siRNA co-delivery system is shown, thereby providing an alternative route for cancer treatment and treatment with treatment with RGDfC-SeNPs@DOX/siRNA resulted in a more significant anticancer activity than the free DOX.
Abstract: Human homeobox protein (Nanog) is highly expressed in most cancer cells and has gradually emerged as an excellent target in cancer therapy, owing to its regulation of cancer cell proliferation, metastasis and apoptosis. In this study, we prepared tumor-targeting functionalized selenium nanoparticles (RGDfC-SeNPs) to load chemotherapeutic doxorubicin (DOX) and Nanog siRNA. Herein, RGDfC peptide was used as a tumor-targeting moiety which could specifically bind to αvβ3 integrins overexpressed on various cancer cells. The sizes of RGDfC-SeNPs@DOX nanoparticles (~12 nm) were confirmed by both dynamic light scattering and transmission electron microscopy. The chemical structure of RGDfC-SeNPs@DOX was characterized via Fourier-transform infrared spectroscopy. The RGDfC-SeNPs@DOX was compacted with siRNA (anti-Nanog) by electrostatic interaction to fabricate the RGDfC-SeNPs@DOX/siRNA complex. The RGDfC-SeNPs@DOX/siRNA complex nanoparticles could efficiently enter into HepG2 cells via clathrin-associated endocytosis, and showed high gene transfection efficiency that resulted in enhanced gene silencing. The in vivo biodistribution experiment indicated that RGDfC-SeNPs@DOX/siRNA nanoparticles were capable of specifically accumulating in the tumor site. Furthermore, treatment with RGDfC-SeNPs@DOX/siRNA resulted in a more significant anticancer activity than the free DOX, RGDfC-SeNPs@DOX or RGDfC-SeNPs/siRNA in vitro and in vivo. In summary, this study shows a novel type of DOX and siRNA co-delivery system, thereby providing an alternative route for cancer treatment.
68 citations
Cites methods from "Folic Acid-Decorated Polyamidoamine..."
...the RGDfC-SeNPs@DOX/siRNA in cells was measured by ICP-MS as previously reported.(24)...
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TL;DR: This review focuses on the recent developments surrounding such PEG/PEO-surface modification of polymeric nanocarriers to promote tumor-targeting capabilities, thereby enhancing efficacy of anti-cancer therapeutic strategies.
Abstract: The success of anti-cancer therapies largely depends on the ability of the therapeutics to reach their designated cellular and intracellular target sites, while minimizing accumulation and action at non-specific sites. Surface modification of nanoparticulate carriers with poly(ethylene glycol) (PEG)/poly(ethylene oxide) (PEO) has emerged as a strategy to enhance solubility of hydrophobic drugs, prolong circulation time, minimize non-specific uptake, and allow for specific tumor-targeting through the enhanced permeability and retention effect. Furthermore, PEG/PEO modification has emerged as a platform for incorporation of active targeting ligands, thereby providing the drug and gene carriers with specific tumor-targeting properties through a flexible tether. This review focuses on the recent developments surrounding such PEG/PEO-surface modification of polymeric nanocarriers to promote tumor-targeting capabilities, thereby enhancing efficacy of anti-cancer therapeutic strategies.
607 citations
TL;DR: The molecular basis of tumour refractoriness should be determined to improve anti-angiogenic therapy and some cancers do not respond well and reduced tumour sensitivity to anti-VEGF signals may occur after long-term treatment.
Abstract: Vascular endothelial growth factors (VEGFs) belong to the platelet-derived growth factor supergene family, and they play central roles in the regulation of angiogenesis and lymphangiogenesis. VEGF-A, the major factor for angiogenesis, binds to two tyrosine kinase (TK) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and regulates endothelial cell proliferation, migration, vascular permeability, secretion and other endothelial functions. VEGFR-2 exhibits a strong TK activity towards pro-angiogenic signals, whereas the soluble VEGFR-1 (sFlt-1) functions as an endogenous VEGF inhibitor. sFlt-1 is abnormally overexpressed in the placenta of preeclampsia patients, resulting in the major symptoms of the disease due to abnormal trapping of VEGFs. The VEGF-VEGFR system is crucial for tumour angiogenesis, and anti-VEGF-VEGFR molecules are now widely used in the clinical field to treat cancer patients. The efficacy of these molecules in prolonging the overall survival of patients has been established; however, some cancers do not respond well and reduced tumour sensitivity to anti-VEGF signals may occur after long-term treatment. The molecular basis of tumour refractoriness should be determined to improve anti-angiogenic therapy.
600 citations
TL;DR: E engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity, and the use of this strategy may enhance the activity of CAR- T cells in individuals with stroma-rich solid tumors.
Abstract: Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
533 citations
TL;DR: The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.
Abstract: Folate receptor-α (FRα) is overexpressed in many cancer cells and is therefore an important therapeutic target: here the X-ray crystal structure of folate-bound FRα is presented, revealing details of the ligand-binding pocket that may be useful in the development of small-molecule inhibitors for anticancer therapy. Folic acid, or folate, is an essential vitamin that is needed for many biological processes, including DNA synthesis, DNA repair and cell division. 'Normal' cells express relatively low amounts of the three folate receptors α, β and γ, but they are commonly overexpressed in cancer cell lines; for this reason, they are potential targets for new chemotherapeutics and cancer-imaging reagents. In this manuscript, the authors solve the X-ray crystal structure of the folate-bound form of human folate receptor α, which mediates folate uptake into cells. The authors map the ligand-binding pocket, providing data that should be useful for the development of new small molecules to target the receptor. Folate receptors (FRα, FRβ and FRγ) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRα, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions1,2,3. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRα antibodies, high-affinity antifolates4,5, folate-based imaging agents and folate-conjugated drugs and toxins6,7,8. To understand how folate binds its receptors, we determined the crystal structure of human FRα in complex with folic acid at 2.8 A resolution. FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRα binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.
526 citations
TL;DR: The resulted HF-IR-780 NPs are a potential theranostic agent for imaging-guided cancer therapy and show good monodispersity, significant stability, and excellent molecular targeting to folate receptor over-expressing MCF-7 cells.
314 citations