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Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Daniel Bobo, Kye J. Robinson, Jiaul Islam, Kristofer J. Thurecht, Simon R. Corrie
Beyond just extending the circulation time of established drugs, polymeric nanoparticles can be developed based on hydrophobic materials that facilitate controlled release of the therapeutic. This is achieved by using slowly degradable functionality that subsequently leads to kinetically driven release of the drug. A long-established polymer nanoparticle that has had significant success is based upon incorporation of leuprolide (a testosterone inhibiting drug) into a polylactide-co-glycolic acid (PLGA) nanoparticle. This drug is sold under the tradename Eligard® and is indicated as an effective treatment for the symptoms of prostate cancer [38]. PLGA is a well-established degradable polymer that slowly decomposes into the constituent monomeric units over controlled time-courses. Another chemotherapeutic, Camptothecin (a DNA topoisomerase I inhibitor), has been encapsulated in cyclodextrin-PEG copolymers to form nanoparticles 20–50 nm in diameter [39]. These nanoparticles (named CRLX101 by licensee Cerulean Pharma Inc.) are administered by intravenous injection and utilize the so-called enhanced permeability and retention effect (EPR) that relies on leaky vasculature in tumors to increase accumulation of the drug molecules at the target of interest. CRLX101 has achieved phase I/II trials in patients with rectal, ovarian, tubal and peritoneal cancer and is an example of classical nanomedicine therapeutics utilizing biocompatible polymeric nanoparticles.
Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers
Published in Expert Opinion on Investigational Drugs, 2022
Raffaella Cioffi, Federica Galli, Emanuela Rabaiotti, Massimo Candiani, Francesca Pella, Giorgio Candotti, Luca Bocciolone, Patrizia De Marzi, Giorgia Mangili, Alice Bergamini
Topotecan is a topoisomerase-1 inhibitor whose role is currently limited as single-agent chemotherapy to recurrent platinum-resistant disease. With the advent of nanoparticle drugs, this chemotherapeutic class gained new potentiality. Nanoparticles deliver drug effects only to cancer so that toxicity on normal tcould be minimal. CRLX101 is an example: a nanoparticle drug conjugate made of a cyclodextrin-containing polymer combining the topoisomerase-I inhibitor, camptothecin (CPT). CPT stabilizes the DNA-topoisomerase I cleavable complex, resulting in single-stranded DNA breaks and eventually cell death. Moreover, low-dose CPT reduces hypoxia-inducible factor 1 (HIF-1), which enhances angiogenesis and metastasization [38,39]. The first phase II study of CRLX-101, as a single agent (cohort A) and with bevacizumab (cohort B), for recurrent PSC showed benefits in both therapeutic regimens: PFS was 4.5 months in Cohort A and 6.5 months in Cohort B. The most commonly reported side effects were nausea, fatigue, and anemia. Although efficacy was only moderate, it met the criteria for an ORR of interest in platinum-resistant disease (>15%). A randomized Phase II or III study is required for any firm conclusion [38,39].
The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: a review study
Published in Nutrition and Cancer, 2021
Sajad Fakhri, Fatemeh Abbaszadeh, Masoumeh Jorjani, Mohammad Hossein Pourgholami
As an active metabolite of Irinotecan, SN38 selectively inhibited ECs proliferation and three-dimensional tube formations. Additionally, it significantly diminished the VEGF and HIF-1α expression of glioma cells in a time- and dose-dependent manner under hypoxic and normoxic conditions via the inhibition of endothelial proliferation, tube formation, and angiogenic cascade in glioma cells (72). As another novel drug of the CPT class, Gimatecan (ST1481), significantly inhibited the tumor angiogenesis even with a shallow dose in the orthotopically implanted melanoma. In-vivo inhibition of vascularization and reducing the expression of pro-angiogenic bFGF in A549 tumor cells associated with the inhibition of the pathway involving Akt were other evidence to prove the antiangiogenic activity of Gimatecan (73). The results of an in-vivo study supported the antiangiogenic therapeutic activities of conjugated CPT–bombesin against cancer by blocking the spread of host mice ECs on matrigel plugs (74). Besides, Lin et al. showed the antiangiogenetic activity of CRLX101 as an investigational CPT-containing nanoparticle drug (75). So, the antiangiogenic and anti-VEGF effects of CPTs play a critical role in combating cancer.
The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy
Published in Expert Opinion on Drug Discovery, 2019
Najah Albadari, Shanshan Deng, Wei Li
CRLX-101(4) is a 20- to 30-nm diameter nanoparticle consisting of water-soluble cyclodextrins-based polymers that contain pendant carboxylate groups, camptothecin (CPT) and alternating repeat polyethylene glycol (PEG) blocks [123]. It was designed to accumulate into solid tumors and slowly release CPT in tumors over an extended period. In addition, it has the advantage of reducing the gastrointestinal (GI) toxicity related to CPT and improving patients’ compliance due to its favorable safety profile [124]. It was demonstrated that CRLX-101 has improved the efficacy of the chemoradiotherapy for locally advanced rectal cancer and when used as monotherapy or in combination therapy [125]. In addition, CRLX101 showed improved efficacy when used alone or in combination therapy with Bevacizumab in metastatic triple negative breast cancer mouse models [126]. CPT, the active moiety in CRLX101, is a potent inhibitor of Topoisomerase I (Topo-I) and HIF-1α. It was originally identified as an HIF-1 inhibitor in 2002 using a cell-based high-throughput screening of approximately 2000 compounds. It inhibits HIF-1α protein accumulation, hypoxic induction of VEGF mRNA and protein expression in hypoxic U251 human glioma cells in a dose-dependent manner. CRLX101 showed higher efficacy and better tolerability in a preclinical mouse model of gastric adenocarcinoma compared to its parent compound CPT and its synthetic analogues Irinotecan (CPT-11) and Topotecan (TPT) [127]. Currently, CRLX101 is being evaluated in phase II clinical trials as in combination therapy with other anticancer drugs for several tumor types [124]. The established dose for CRLX101 concluded from phase I clinical trial is 15 mg/m2 to be given intravenously every 2 weeks [124]. The preferential safety profile of CRLX101 was also confirmed in a pilot trial using the same recommended dose in patients with chemotherapy-refractory gastroesophageal cancer [125,128].