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Investigational Nanomedicines in 2016: A Review of Nanotherapeutics Currently Undergoing Clinical Trials *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Joseph M. Caster, Artish N. Patel, Tian Zhang, Andrew Wang
Nippon Kayaku Inc. currently has two polymeric nanoparticle drugs in development, NK012 and NK015. NK012 is a polymeric formulation of SN-38 (the active metabolite of the topoisomerase inhibitor irinotecan). This drug has completed two phase I studies (results pending) and there are currently several ongoing phase II trials [35]. NK015 is a polymeric formulation of paclitaxel. Similar to other nanoformulations of paclitaxel, early phase trials are showing that NK015 has a more favorable toxicity profile than solvent-based Taxol and may have increased efficacy [36–38]. There is currently an ongoing phase III study comparing NK015 to Cremophor-based paclitaxel for the treatment of metastatic breast cancer. In addition to these two compounds, there are preclinical data for a third compound, NK911. This is a polymeric formulation of doxorubicin, which appears to have lower stability and more rapid release than the approved liposomal doxorubicin formulation, Doxil [39]. This drug has completed phase I and has a good safety profile [40]. but there are no current or ongoing studies, and it is unclear if further clinical development will be pursued.
Medication: Nanoparticles for Imaging and Drug Delivery
Published in Harry F. Tibbals, Medical Nanotechnology and Nanomedicine, 2017
NK012 is another polymeric micelle drug formulation loaded with the iri-notecan metabolite SN-38, with two Phase II clinical trials for breast and lung cancer (2009). SN-38 (7-ethyl-10-hydroxy-camptothecin) is a biologically active metabolite of the prodrug irinotecan (CPT-11), which binds to and inhibits topoisomerase I by stabilizing the cleavable complex between topoi-somerase I and DNA, resulting in DNA breaks, inhibition of DNA replication, and apoptosis. SN-38 has been reported to exhibit up to 1000-fold more cytotoxic activity against various cancer cells in vitro than irinotecan. This SN-38-releasing nanodevice is constructed by covalently attaching SN-38 to the block copolymer PEG-PGlu, followed by self-assembly of amphiphilic block copolymers in an aqueous milieu. This formulation increases the water solubility of SN-38 and allows the delivery of higher doses of SN-38 than those achievable with SN-38 alone [183].
Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM–camptothecin conjugate
Published in Drug Delivery, 2018
Pengkai Ma, Yi Sun, Jianhua Chen, Hongpin Li, Hongyu Zhu, Xing Gao, Xinning Bi, Yujie Zhang
Smart controllable drug release from nanocarriers in tumor cells remains another crucial issue. Before nanocarriers are taken up by tumor cells, they release most of the loaded drug into the systemic circulation, ultimately leading to systemic toxicity and poor anticancer efficacy (Karimi et al., 2016; You et al., 2017). Tumor cell microenvironment shows significant differences from it of normal cells (Danhier, 2016; Chen et al., 2017). The intracellular concentration of glutathione (GSH) is approximately 10 mM, which is 5000-fold higher than that in extracellular environments. This significant difference in GSH levels has been explored as a trigger for drug release inside target cells with reductive sensitivity (Stephen et al., 2014; Guo et al., 2015). The introduction of GSH-triggered disulfide cross-links to polymer nanocarriers can stabilize carriers against hydrolytic degradation and efficiently initiate drug release once the carriers are internalized in the target cells (Zou et al., 2016). However, these nanomedicines generally require sophisticated designs and complex fabrication procedures. The few clinically successful nanomedicines have shown that in addition to efficacy and safety, simplicity, and cost play a decisive role in their translation into therapeutic products (Hofmann-Amtenbrink et al., 2015; Hare et al., 2016). Polymeric conjugates may address these issues, since a few chemotherapeutic drugs conjugated with various functional polymers have been approved for clinical trials and even for the market, including N-[2-hydroxylpropyl] methacrylamide (HPMA)-doxorubicin (PK1/FCE28068) (Seymour et al., 2009) and poly-glutamacid (PGA)-SN38 (NK012) (Hamaguchi et al., 2010).
Tetrac-decorated chitosan-coated PLGA nanoparticles as a new platform for targeted delivery of SN38
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Mona Alibolandi, Sara Amel Farzad, Marzieh Mohammadi, Khalil Abnous, Seyed Mohammad Taghdisi, Fatemeh Kalalinia, Mohammad Ramezani
SN38 (7-ethyl-10-hydroxy camptothecin) is an antineoplastic agent belonging to camptothecin (CPT) family which is a highly potent topoisomerase 1 inhibitor [13] which disrupts the structure and function of DNA [14] . Previous studies demonstrated that SN38 is the active metabolite of irinotecan (CPT-11) and it is 100–1000 folds more potent than CPT-11 [15–17]. So that liver activation is not required, thereby interpatient variability is eliminated [18]. Despite the promising chemotherapeutic effects of SN38, its clinical application is relatively hindered by its very low solubility in pharmaceutically accepted media and little stability in physiological pH [16,19]. To overcome such limitations, studies are moved towards attachment of SN38 to hydrophilic polymeric moieties such as EZN-2208 which is PEGylated SN38 in phase 2 clinical trials [20] or its loading into nanoparticles such as liposomes [21], polymeric micelles (NK012 in phase 1 clinical studies) [22] or carbon nanotubes [23]. Such strategies could preserve the stability of the drug moiety while prolonging its blood circulation to enhance the tumour accumulation [15]. In the present study, we loaded SN38 into a poly (lactide-co-glycolide) (PLGA) matrix which its surface was coated with chitosan. Previous studies demonstrated that such polymers preserve the drug moieties from enzymatic degradation and provide physicochemical stability [24]. PLGA is a synthetic polymer which is FDA approved for use in biomedical devices [25]. In various studies, it was also used as a carrier for cytotoxic drugs [24,26,27]. Mehdizadeh et al. [28] designed a biotin-decorated PLGA nanoparticles encapsulating SN38. However, the main challenges of PLGA-based formulations is the burst release of the cargo. To overcome the limitation, we coated the particle surface with chitosan as previously suggested by Chen et al. [29]. Chitosan is a natural polysaccharide polymer [30] extensively studied in drug delivery applications [25–27]. In addition to provide a sustained release pattern while coated onto the surface of PLGA nanoparticles, its positive charge enhances the cellular uptake of the drug-loaded particles according to the negative charge of the cell membrane [31].