Current Trends in ATRA Delivery for Cancer Therapy
Abstract
:1. Introduction
2. From Vitamin A to ATRA
3. ATRA AND CANCER: Successes and Failures
4. ATRA Delivery Strategies: What We Got in the Clinics
5. ATRA Delivery Strategies: Moving Forward
5.1. Oral Administration
5.2. Intravenous Administration
5.2.1. Stealth Strategy
5.2.2. Passive Tumor Accumulation—Enhanced Permeability Retention Effect
5.2.3. Active Targeting—Surface Functionalization with Specific Targeting Ligands
5.2.4. Cellular Uptake and Endosomal Escape
Positive Charge Surface
Proton-Sponge Effect
5.2.5. Stimuli-Responsiveness
5.3. Inhalable Administration
5.4. Alternative Administration
Tumor | ATRA Delivery System | Model | Pros | Cons | Ref |
---|---|---|---|---|---|
Acute Promyelocytic Leukemia | ATRA-loaded microemulsion O/W | Porcine intestinal membrane | Oral delivery of ATRA to enhance drug bioavailability and intestinal absorption | Only in vitro studies | [104] |
DOX-loaded LMWH–ATRA nanoparticles (DHR nanoparticles) negatively charged | Cell lines: HL-60 and MCF-7; mouse model | Lower risk of bleeding and thrombocytopenia/selective uptaking endocytosis mediated | [137] | ||
ATRA-loaded in Cholesteryl Butyrate Solid Lipid Nanoparticles | Cell lines: HL-60, Jurkat, and THP1 | High encapsulation efficiency over and enhanced anticancer activity when compared to the free ATRA | Only in vitro studies | [96] | |
Breast cancer | ATRA-loaded Pluronic F127 micelles | Cell lines: 4T1, MDA-MB-231, EMT6, and BT474; Mouse model | Biocompatibility, high ATRA loading content and synergistic effects with Cisplatin | No biodistribution studies | [98] |
Human serum albumin (HSA)-based nanoparticles for the co-delivery of ATRA and Paclitaxel (PTX) | Cell line: 4T1 | Increase of individual drug’s efficacy both in vitro and in vivo, inhibition of the migration and invasion of cancer cells in vivo (reduction of cancer cell MMPs activity and of EMT process) | [115] | ||
Hyaluronic acid (HA) nanoparticle with an inner hydrophobic core containing ATRA and the anticancer drug Gambogic acid (GA) | Cell lines: MCF-7 and KB31 | HA receptor-mediated endocytosis improves the internalization into the tumor cells | [146] | ||
Nanoparticles co-delivery strategy of an ATRA and DOX based-therapy | Cell line: MDA-MB-231 | Selective uptaking | [127] | ||
Nanoparticles encapsulating ICG dye with coumarin-containing ATRA (AC), modified with the targeted ligand cyclic (Arg-Gly-Asp-D-Phe-Lys) (cRGD) peptide on the surface | Cell lines: MCF-7 and MDA-MB-231 | Combination of photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy | Only in vitro studies | [184] | |
Amphiphilic zein-chondroitin sulfate (ChS)-based copolymeric micelles containing ATRA/Etoposide | Cell line: MCF-7; mouse model | Enhancing internalization in vitro and reducing tumor volume, decreasing proliferation, and promoting necrosis in vivo | No PK and biodistribution studies | [134] | |
Gastric cancer | CD44/CD133 antibodyconjugated ATRA-loaded nanoparticles | Cell lines: MKN-45 and NCI-N87 | Specific target of cancer stem cells by using membrane markers | Difficulty reaching the targeted site in vivo | [142] |
ATRA/Sorafenib/miR-542-3p co-delivery in PEGylated Gelucire-based Solid Lipid Nanoparticles | Cell line: MGC-803; mouse model | Enhanced anti-tumor efficacy of drug co-loading | No biodistribution studies | [121] | |
Glioblastoma | ATRA-loaded poly(diol citrate) wafers | Cell line: U87MG | Long-term treatment in vitro and reduced ATRA isomerization and degradation | Duration of release in vivo is not known | [197] |
3D bioprinted hydrogel mesh loaded with ATRA | Cell line: U87MG | Controlled release and immobilization of DDS close to tumor site | Biocompatibility of the construct in the brain in vivo | [195] | |
CARD-B6 NPs loaded with ATRA, DOX and CA4 | Cell line: U87MG; Mouse model | Controlled release by using different peptide tools and a tractable DDS by MRI | [178] | ||
Liver cancer | Poly(amidoamine) (PAMAM) dendrimers | Cell line: HepG2 | pH-responsive DDS and enhanced cellular uptake | Only in vitro studies | [167] |
Lung cancer | ATRA/Genestein-loaded hybrid lipid nanocore-protein shell | Cell line: A549; Mouse model | Stable inhalable dry powder | [191] | |
ATRA/Paclitaxel-PEG-b-PBLA micelles (pH and redox dual-responsive) | Cell line: A549; Mouse model | Prolonged circulation time, reduced nonspecific protein adsorption effective delivery to the tumor site and within the tumor cells, controlled drug release, and negligible systemic toxicity | No biodistribution studies | [168] | |
DOTAP liposomes loaded with ATRA | Mouse model | Higher half-life, Cmax and a lower CL of ATRA loaded liposomes compared to the mice treated with free ATRA. | Strong immune response | [157] | |
ATRA-loaded niosomes | Inhalable DDS to enhance drug localization in the targeted site | Only in vitro studies | [190] | ||
Lymphoma | ATRA nanoparticles constituted by a fusion protein scaffold comprising apolipoprotein A1 (APOA1) and a single chain variable antibody fragment (scFv) against CD20 | Lymphoma | Targeted therapy thanks to selective uptake | Only in vitro studies | [150] |
Melanoma | Polymeric micelles of hyaluronic acid – ATRA for the co-delivery of Paclitaxel and ATRA | Cell line: B16F10; Rat model | Redox-responsive drug release and higher CD44-dependent cellular uptake in vitro, and prolonged circulation time | Antitumor efficacy of the constuct is not known in vivo | [171] |
CD20-antibody conjugated PLGA nanoparticles | Cell lines: A375 and WM266-4 | Better targeting and stronger inhibitory effects against melanoma-initiating cells (CD20+) with respect to CD20- cells | Only in vitro studies | [140] | |
Lipid-coated Hollow Mesoporous Silica Nanoparticles-ATRA/Doxorubicin/IL-2 | Mouse model | Excellent encapsulation capacity, satisfactory stability, favorable biodistribution and low systemic toxicity | [99] | ||
Ovarian cancer | Polymer-oil nanostructued carrier (PONC) | Cell line: SKOV-3 | Controlled and sustained release profile, biological stability and increased cellular uptake by efficient drug permeation | Only in vitro studies | [152] |
Pancreatic ductal adenocarcinoma | PEGylated polyethylenimine-coated gold nanoparticles for the co-delivery of ATRA and siRNAHSP47 | Cell lines: Pancreatic cancer primary cells; Mouse model | pH-responsive DDS, stability in the systemic circulation, negligible system toxicity, and effective accumulation in the tumor site | Quick clearance of the DDS | [173] |
Polyamidoamine (PAMAM) dendrimer-coated magnetic iron nanoparticles (DcMNPs) | Cell lines: ductal pancreatic cells and pancreatic stellate cells (PSCs) | Magnetic nanoparticles can be targeted to tumor site in a magnetic field and they successfully taken up by pancreatic cancer and PSC cells | Only in vitro studies | [176] | |
Thyroid cancer | ATRA/Sorafenib-loaded (PEG–PLGA) polymeric micelles | Cell line: FTC-133; Mouse model | Prolonged circulation time, effective delivery to the tumor site and within the tumor cells, controlled drug release, and negligible system toxicity | [119] |
5.5. Patents
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Nano-fibular nanoparticles polymer-ATRA conjugate for sustained dermal delivery | WO2016210087A1; US2018185513A1 | 23rd June 2015 | 29th December 2016 (WO2016210087A1); 5th July 2018 (US2018185513A1) | USA | PCT |
ATRA-loaded liposomal aerosols for delivery to the lungs | US6334999B1 | 27th August 1999 | 1st January 2002 | USA | - |
ATRA/TGFβ-loaded (PLGA) polymeric nanoparticles for the treatment of Type 1 Diabetes Mellitus | WO2015109245A1; US2016338984A1; US10105334B2 | 17th January 2014 | 23rd July 2015 (WO2015109245A1); 24th November 2016 (US2016338984A1); 23rd October 2018 (US10105334B2) | USA | PCT |
ATRA quasicrystal-loaded liposomes for the treatment of solid tumors | CN109364027A | 12nd December 2018 | 22nd February 2019 | China | - |
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ATRA/aPD-L1-loaded (PLGA-PEG) polymeric nanoparticles for the treatment of oral dysplasia and oral squamous carcinoma | CN110623942A | 30th September 2019 | 31st December 2019 | China | - |
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Giuli, M.V.; Hanieh, P.N.; Giuliani, E.; Rinaldi, F.; Marianecci, C.; Screpanti, I.; Checquolo, S.; Carafa, M. Current Trends in ATRA Delivery for Cancer Therapy. Pharmaceutics 2020, 12, 707. https://doi.org/10.3390/pharmaceutics12080707
Giuli MV, Hanieh PN, Giuliani E, Rinaldi F, Marianecci C, Screpanti I, Checquolo S, Carafa M. Current Trends in ATRA Delivery for Cancer Therapy. Pharmaceutics. 2020; 12(8):707. https://doi.org/10.3390/pharmaceutics12080707
Chicago/Turabian StyleGiuli, Maria Valeria, Patrizia Nadia Hanieh, Eugenia Giuliani, Federica Rinaldi, Carlotta Marianecci, Isabella Screpanti, Saula Checquolo, and Maria Carafa. 2020. "Current Trends in ATRA Delivery for Cancer Therapy" Pharmaceutics 12, no. 8: 707. https://doi.org/10.3390/pharmaceutics12080707