Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages
TL;DR: Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model, suggesting targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.
About: This article is published in Acta Pharmaceutica Sinica B.The article was published on 2021-09-30 and is currently open access. It has received 14 citations till now. The article focuses on the topics: Nanocarriers & Folate receptor.
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TL;DR: In this paper , a unique, synergistic strategy is evaluated to improve the therapeutic efficacy of a DNA damage response (DDR) inhibitor (AZD-2461) and a diketopyrrolopyrrole-based NIR-II fluorescent photosensitizer DT.
20 citations
TL;DR: In this article , a review of state of the art in polymeric micelle as a nano-drug delivery system for chemotherapeutics and their efficiency in cancer management is presented.
12 citations
TL;DR: In this article , the double bond on the side group of carboxymethyl chitosan was polymerized and cross-linked with N-N′-bis(acryloyl) cysteamine (BAC), containing a disulfide bond, and modified with folic acid (FA) to obtain nanogels for the targeted delivery of doxorubicin (DOX).
Abstract: Here, glycidyl methacrylate (GMA) was used for modification of carboxymethyl chitosan (CMCS). The double bond on the side group of CMCS was polymerized and cross-linked with N-N′-bis(acryloyl) cysteamine (BAC), containing a disulfide bond, and modified with folic acid (FA) to obtain nanogels for the targeted delivery of doxorubicin (DOX). Effectiveness of DOX delivery and release were subsequently investigated. The drug encapsulation efficiency (EE) and loading capacity (LC) of DOX were 94.77 ± 0.83% and 15.6 ± 0.12%, respectively. The particle size of the GCMCS-FA-DOX nanoparticles loaded with DOX was 220.4 ± 38.4 nm. The experimental results showed that GCMCS-FA-DOX had a high glutathione and pH response performance. GCMCS-FA-DOX showed an improved inhibitory effect on tumor cell proliferation compared to free DOX. GCMCS-FA-DOX significantly improved the efficiency of drug uptake by cells, and the cytotoxicity of GCMCS-FA-DOX in HCT-116 tumor cells was higher than that in HepG-2 tumor cells.
7 citations
TL;DR: FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors in vivo, and retained folate binding activity and could effectively target folate receptor positive tumors in vivo.
Abstract: Folic acid (FA) is one of the most widely utilized small-molecule ligands for cancer targeted drug delivery. Natural IgM was recently found to avidly absorb on the surface of FA-functionalized liposomes (FA-sLip), negatively regulating the in vivo performance by efficiently activating complement. Herein, FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors in vivo. The FA moiety along with the bound IgM was restricted to the highly curved rim of lipodiscs, leading to IgM incapability of presenting the membrane-bound conformation to trigger complement activation. The C1q docking, C3 binding, and C5a release were blocked and accelerated blood clearance phenomenon was mitigated of FA-Disc. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors in vivo. The present study provides a useful solution to avoid the negative regulation by IgM and achieve FA-enabled targeting by exploring disc-shaped nanocarriers.
7 citations
22 Aug 2022
TL;DR: The first enzyme-activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors are reported, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment.
Abstract: Abstract Increased levels of tumor‐associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme‐activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g., CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g., neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin‐activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment.
5 citations
References
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TL;DR: It is shown that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-β inhibitor to increase the permeability of the tumours.
Abstract: Drug-loaded polymeric micelles with a diameter of 30 nm can penetrate poorly permeable tumours to achieve an antitumour effect.
2,026 citations
TL;DR: Developing and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors and initial clinical data indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL.
Abstract: We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL) In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic
1,029 citations
TL;DR: This work discusses how these barriers can be overcome through innovative nanomedicine design and through creative manipulation of the tumour microenvironment.
Abstract: Cancer nanomedicines approved so far minimize toxicity, but their efficacy is often limited by physiological barriers posed by the tumour microenvironment. Here, we discuss how these barriers can be overcome through innovative nanomedicine design and through creative manipulation of the tumour microenvironment.
686 citations
TL;DR: The results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.
Abstract: The large size of many novel therapeutics impairs their transport through the tumor extracellular matrix and thus limits their therapeutic effectiveness. We propose that extracellular matrix composition, structure, and distribution determine the transport properties in tumors. Furthermore, because the characteristics of the extracellular matrix largely depend on the tumor–host interactions, we postulate that diffusion of macromolecules will vary with tumor type as well as anatomical location. Diffusion coefficients of macromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photobleaching. For the same tumor types, diffusion of large molecules was significantly faster in CW than in DC tumors. The greater diffusional hindrance in DC tumors was correlated with higher levels of collagen type I and its organization into fibrils. For molecules with diameters comparable to the interfibrillar space the diffusion was 5- to 10-fold slower in DC than in CW tumors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.
599 citations
TL;DR: In vitro results demonstrated that the mixed micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake and after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity.
591 citations