Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Eleonora Russo
 + 3250 word(s) 3250 2021-06-21 10:51:01 |
2 update references and layout
Amina Yu
 Meta information modification 3250 2021-06-22 03:09:22 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Russo, E. Tyrosine Kinase Inhibitors in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/11082 (accessed on 20 April 2024).
Russo E. Tyrosine Kinase Inhibitors in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/11082. Accessed April 20, 2024.
Russo, Eleonora. "Tyrosine Kinase Inhibitors in Cancer" Encyclopedia, https://encyclopedia.pub/entry/11082 (accessed April 20, 2024).
Russo, E. (2021, June 21). Tyrosine Kinase Inhibitors in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/11082
Russo, Eleonora. "Tyrosine Kinase Inhibitors in Cancer." Encyclopedia. Web. 21 June, 2021.
Tyrosine Kinase Inhibitors in Cancer
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms22126538

Intracellular protein tyrosine kinases, including Abelson (Abl), Src, JNK and many others, play a pivotal role in signal transduction pathways and cancer development, being highly activated in malignant tumor cells, but having very low activity and expression in normal cells. Consequently, in the last thirty years, many small molecule tyrosine kinase inhibitors (TKIs) have entered in clinical trials and were approved to treat hematologic and non-hematologic tumors, thus improving cancer treatment. In particular, the greatest progress has been made with the use of TKIs in the treatment of chronic myeloid leukemia (CML).

tyrosine kinase inhibitors nanoparticles drug delivery EPR

1. Introduction of Tyrosine Kinase Inhibitors

Intracellular protein tyrosine kinases, including Abelson (Abl), Src, JNK and many others, play a pivotal role in signal transduction pathways and cancer development, being highly activated in malignant tumor cells, but having very low activity and expression in normal cells [1]. Consequently, in the last thirty years, many small molecule tyrosine kinase inhibitors (TKIs) have entered in clinical trials and were approved to treat hematologic and non-hematologic tumors, thus improving cancer treatment. The majority of these molecules are ATP-competitive inhibitors and are not selective, acting also on receptor tyrosine kinases (in particular, platelet-derived growth factor receptor, PDGFR, and vascular endothelial growth receptor, VEGFR) or other intracellular kinases with different selectivity and potency. Unfortunately, all of these new compounds presented sub-optimal properties such as poor solubility (very high pH-dependent solubility), low oral bioavailability and severe adverse effects, which limited their clinical application; in addition, the onset of resistance became the biggest obstacle in clinical application for some of the new molecules (in particular for Imatinib,Figure 1).

Ijms 22 06538 g001 550

Consequently, in recent years many efforts have been made to find new molecules (e.g., Asciminib, Flumatinib; Figure 1) active on resistant CML (in particular on T315I mutation), for the treatment of different diseases (e.g., Ruxolitinib; Figure 1) currently without an effective therapy. In Table 1, selected TKIs (the most important for CML treatment and more recent and innovative than other ones) and their applications are reported. Issues related to solubility and resistance onset could be solved using safe and efficient delivery vehicles, that could improve the therapeutic efficacy, minimize toxicity, ameliorate tumor targetability and decrease drug resistance [2][3].

Consequently, in recent years many efforts have been made to find new molecules (e.g., Asciminib, Flumatinib;Figure 1) active on resistant CML (in particular on T315I mutation), for the treatment of different diseases (e.g., Ruxolitinib;Figure 1) currently without an effective therapy. InTable 1, selected TKIs (the most important for CML treatment and more recent and innovative than other ones) and their applications are reported. Issues related to solubility and resistance onset could be solved using safe and efficient delivery vehicles, that could improve the therapeutic efficacy, minimize toxicity, ameliorate tumor targetability and decrease drug resistance [2][3].

Table 1. Selected TKIs, their molecular targets, FDA approval years, number of clinical trials and treated diseases.
Compound Target Number of Clinical Trials Diseases FDA Approval
Imatinib Abl, PDGFR, Kit 754 CML, GIST, GVHD, many hematological and solid tumors 2001
Dasatinib Abl, PDGFR, Kit, Src 320 CML, ALL, lymphoma, NSCLC and others solid tumors 2006
Nilotinib Abl, PDGFR, c-Kit, LCK, EPHA3, EPHA8, DDR1, DDR2, MAPK11, ZAK 219 CML, ALL, GIST 2007
Ponatinib Abl, Src, FGFR, PDGFR, VEGFR, 67 CML, ALL 2012
Asciminib Abl 13 CML //
Flumatinib Abl, PDGFR, c-Kit, CSFR 5 CML //
Sunitinib PDGFR, Kit, FLT3, VEGFR, CSF1R 610 RCC, GIST 2006
Sorafenib PDGFR, c-Kit, FLT3, VEGFR, B-Raf 870 RCC, liver and thyroid cancers 2007
Axitinib Abl, PDGFR, VEGRF, c-Kit 161 RCC 2012
Ruxolitinib JAK1, JAK2 258 Myelofibrosis, polycythemia vera, GVHD, many other different diseases 2011

Imatinib (IM, Gleevec®, Glivec®) was approved for CML in 2001 and today represents the first-line therapy for this type of hematological tumor, being able to block phosphorylation of Bcr-Abl, a fusion protein kinase which plays a fundamental role in CML development [4]. As IM inhibits PDGFR and c-Kit, two other transmembrane TKs, it has been approved as frontline therapy for: (i) gastrointestinal stromal tumors (GIST), characterized by mutated and over-expressed c-Kit or PDGFR-b [5]; (ii) other myeloid malignancies and hypereosinophilic syndromes and (iii) systemic mastocytosis [6][7] Most of them are obviously focused on CML, but also on solid tumors, such as acute lymphoblastic lymphoma (ALL), GIST, melanoma, sarcoma, glioblastoma and papillary thyroid cancer; interestingly, some trials concern asthma (NCT01097694), chronic graft-versus-host disease (GVHD) (NCT01862965), steroid-refractory sclerotic/fibrotic type GVHD (NCT01898377), multiple sclerosis (MS) (NCT03674099) and COVID-19 (NCT04422678), this compound having good immunosuppressive properties.

Currently, 350 clinical trials (63 in recruitment) regarding Dasatinib are focused on CML, ALL, Hodgkin and non-Hodgkin lymphoma, neck, head, breast, NSCLC, melanoma, mesothelioma, ovarian, colorectal, glioblastoma and CNS tumors (Table 1). In addition, Dasatinib, also acting on PDGFR, Kit, Src, Tek and Btk [8], could be useful as an immunosuppressive agent for immunological disorders [9]. Nilotinib is currently being studied in 219 clinical trials (41 in recruitment,Table 1) to evaluate its efficacy in CML, ALL, GIST and sarcoma (soft tissue sarcoma) patients, but also Huntington’s (NCT03764215), Parkinson’s (NCT02954978) and different forms of dementia pathologies (NCT02947893, NCT04002674).

Sorafenib (Figure 1) is an approved pankinase inhibitor able to target the Ras/Raf/Mek/Erk cascade pathway, PDGFR, VEGFR1/2 and the c-Kit receptor, and to block cell proliferation of different solid tumors; in particular, hepatocellular carcinoma (HCC) [10]. However, its long-term application in clinical practice was hampered by serious dermal toxicity and drug resistance, low water solubility and the first-pass effect [11] and consequent low drug concentration in tumor tissue. In addition, it can induce paradoxical activation of the MAPK pathway in both malignant and normal stromal cells [12] and this fact in hepatic stellate cells (HSCs) leads to their activation with consequent liver damage. Other pankinase inhibitors (e.g., Sunitinib and Axitinib;Figure 1) have been more recently approved for advanced RCC, unresectable HCC, thyroid cancer and GIST, and many other clinical trials are ongoing also on different solid tumors and leukemia types [13][14].

Seventy-six clinical trials (31 in recruitment,Table 1) focused on CML, ALL and different solid tumors (as NSCLC, GIST, glioblastoma, breast and many others) are reported for Ponatinib, (Iclusig,Figure 1) [15], approved in 2012 for CML treatment. In 2013, the FDA temporarily suspended Ponatinib sales because of the risk of life-threatening blood clots and severe narrowing of blood vessels, but at the end of the same year, this suspension was partially lifted.

Very recently, Novartis announced the results of a phase III ASCEMBL study (multicenter, open-label, randomized study) regarding Asciminib (ABL001,Figure 1), a new Abl allosteric inhibitor; the study evaluated Asciminib administration in adult patients with Philadelphia chromosome-positive CML in chronic phase, previously treated with two or more TKIs for 24 weeks [16][17][18]. On the basis of these interesting results, the FDA has granted Fast Track designation for Asciminib. Now, 14 clinical trials (two of them completed,Table 1) are focused on this compound (alone or in association with IM or Nilotinib) for CML and other leukemic patients; only one clinical trial is focused on asthma treatment (NCT03549897).

Flumatinib (HHGV678,Figure 1) is an orally bioavailable TKI, recently approved in China [19]; it inhibits the wild-type and mutated Bcr-Abl, PDGFR and mast/stem cell growth factor receptor (SCFR and c-Kit). Up to date, five clinical trials (one completed,Table 1) regarding only CML are in progress.

Ruxolitinib (Jakafi,Figure 1) is a selective JAK1 and JAK2 inhibitor approved for myelofibrosis (2011), polycythemia vera (2014) and GVHD in adult and pediatric patients (2019), but now it is also under study for COVID-19 (NCT04414098, NCT04359290, NCT04348071), atopic dermatitis (NCT039208529) and vitiligo (NCT04530344) (Table 1).

Although new compounds are continuously placed on the market and many are effective against different mutations, problems regarding poor solubility, resistance and severe side effects are not completely overcome. In part, the evolutionary probability of resistance can also be overcome with the association of two or more compounds, but this approach does not seem to be conclusive; consequently, the advent of nanotechnologies seems to be of great importance. In addition, it is also possible that the administration of one single nanoparticle containing several drugs may be more effective than the administration of several nanoparticles each containing one compound [20].

2. Nanoparticles of Tyrosine Kinase Inhibitors

A major part of these new nanoformulations have been patented in the last ten years [21][22]; in general, IM and Dasatinib represent the most studied compounds, whereas new molecules, such as Asciminib, Axitinib and others, are less investigated. Interesting results have been obtained for Sorafenib, Ponatinib and Nilotinib, as reported below. Regarding the routes of administration, these nanocarriers are usually injected intravenously; recent reports describe alternative administration routes thorough intratecal [23] and subcutaneous injection [24].

2.1. Imatinib

IM was the first molecule in this series to be nanoformulated and received great interest from researchers. A lot of papers reported the use of IM-encapsulated NPs and demonstrated their efficacy; some of these studies are reported as examples of IM delivery using nanotechnology.

2.2. Dasatinib

Many patents focus on Dasatinib nanoformulations and most of them are innovative and very recent [25][26][27]. As previously reported, a major problem for oral administration of Dasatinib is its poor bioavailability caused by a low solubility, inappropriate partition coefficient, low drug permeation through lipid membrane, first-pass metabolism, P-glycoprotein-mediated efflux and drug degradation in the gastrointestinal tract due to the pH of the stomach or enzymatic degradation [28]. Animal data suggest that, due to an extensive first-pass effect, the bioavailability of Dasatinib is about 14–34%. Thus, limited aqueous solubility is the bottleneck for the therapeutic outcome of Dasatinib. The majority of Dasatinib nanoformulations have been developed to treat CML cell lines, but as reported below, also for solid tumor treatment. In addition, in the last years Dasatinib-loaded NPs have been developed for different diseases, in particular ocular diseases (proliferative vitreoretinopathy, PVR) [29][30].

2.3. Nilotinib

Nilotinib (Tasigna®) is a recent pankinase inhibitor used for IM-resistant CML. In addition, a number of patents have been published on nanoformulations prepared to ameliorate Nilotinib activity and efficacy [31][32].
Very recently, Koehl et al. [33] explored the potential of lipid vehicles to improve the bioavailability of hydrophobic drugs such as Nilotinib, comparing a chase-dosing approach and lipid suspensions. To improve the dissolution kinetics, gastrointestinal absorption and bioavailability of some TKIs (including Nilotinib), Jesson et al. [34] prepared hybrid NPs, consisting of amorphous TKI embedded in a polymer matrix; these nanosystems displayed an increase in Nilotinib release rate in both simulated gastric fluid and intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. The prepared hybrid NPs represent a promising approach to improve drug dissolution rate, gastrointestinal absorption and bioavailability following oral administration [34].
Other targeted nanoformulations have been developed to minimize the resistance phenomenon and reduce cytotoxicity, not only for CML treatment, but also for application in different solid tumors. Recently, Fan et al. [35] prepared collagenase I and retinol co-decorated polymeric micelles that possess a nanodrill-like and HSCs-targeting function based on poly(lactic-co-glycolic)-poly(ethyleneglycol)-maleimide (PLGA-PEG-Mal) (named CRM) for liver fibrosis treatment. These particular functionalized NPs could realize excellent accumulation in fibrotic liver and accurate targeting to activated HSCs in a mouse hepatic fibrosis model. Moreover, CRM loaded with Nilotinib showed optimal antifibrotic activity, suggesting that CRM is an efficient carrier for liver fibrosis drug delivery; in this study, the authors demonstrated that collagenase I, decorating NPs, could be a new strategy for building a more efficient HSCs-targeting nanodrug delivery system [35].
In another work, wool-like NPs were developed to treat CML; in detail, a poly(ε-caprolactone) (PCL) nanosystem, composed of a biodegradable pH-sensitive core releasing Nilotinib and an enzyme-sensitive outer shell releasing IM mesylate, were prepared. This combinatorial delivery showed reduced IC50 values on leukemia cells compared to single free drugs administration. In addition, in vitro results evidence a consistent drug release and a more therapeutic efficiency at a low dose with respect to the single-drug nanoformulation, confirming that both drugs reached the target cell precisely, maximizing the cytotoxicity and minimizing drug cell resistance [36].

2.4. Ponatinib

As reported for Nilotinib, many patents were focused on nanoformulation of Ponatinib [31][32][37] and different authors published various methods to obtain Ponatinib formulations [38].
Targeted Ponatinib-loaded NPs have been recently investigated to evaluate their biological effect on osteosarcoma cell lines. In detail, Zinger et al. [39] reported the design and synthesis of biomimetic/targeted NPs incorporating Ponatinib. These SLNs incorporate membrane proteins purified from activated leukocytes that enable immune evasion and enhanced targeting of inflamed endothelium. The NP formulations showed promising dose−response results in two different murine osteosarcoma cell lines, indicating efficient Ponatinib loading and a possible application for numerous therapeutic agents with toxicity profiles.
Kallus et al. [40] encapsulated Ponatinib and Nintedanib into liposomes to obtain increased tumor accumulation/specificity and reduced side effects. Different methods of drug loading were tested and, interestingly, in an FGFR inhibitor-sensitive murine osteosarcoma transplantation model (K7M2), only liposomal, but not free, Ponatinib showed a significant tumor growth inhibition with reduced side effects.

2.5. Sunitinib

Regarding Sunitinib, a major part of efforts has been focused on the production of polymeric nanoparticles. In addition, a more recent Chinese patent is focused on PLA–PEG–PLA Sunitinib NPs [41].
Otroi et al. [42] prepared Sunitinib-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate acid) NPs, obtaining dry powders after spray drying, and evaluated their cytotoxicity effects on A549 cells by MTT assay. This formulated inhalable powder could represent a promising medication for local therapy of lung cancer.
Nanopolymeric pharmaceutical excipients, such as CS nanoparticles, were synthesized and evaluated as in vitro drug release systems for Sunitinib [43].
Shi et al. [44] developed different targeted liposome formulations able to treat resistant breast cancer in vitro. In detail, targeted Sunitinib plus vinorelbine liposomes showed a good inhibitory effect on resistant MCF-7/Adr cells and represented a novel type of nanoformulations, which could accumulate in the resistant breast cancer cells.
In another study, the same authors developed a novel type of targeted liposomes by modifying a mitochondriotropic material (i.e., D-a-tocopheryl polyethylene glycol 1000 succinate–triphenylphosphine conjugate, TPGS1000-TPP), to encapsulate Sunitinib. Biological in vitro evaluations were carried out, in breast cancer cell lines (MCF-7 and MDA-MB-435S) and in vivo in mice. Targeted drug liposomes were internalized via cellular uptake and accumulated in the mitochondria of invasive breast cancer cells, inducing acute cytotoxic injury and apoptosis [45]. Interestingly, other studies showed successful development of Sunitinib-loaded PLGA-NPs not only for cancer therapy, but also for neovascular age-related macular degeneration disease [46].

2.6. Sorafenib

To overcome the delivery problems previously presented for Sorafenib, many efforts have been made to obtain different NPs, particularly SLN [47], graphene nanosheets [48], PSi and AuNPs in a polymeric nanocomplex [49], PLA NPs [50], hydroxypropylmethylcellulose (HPMC) or polyvinyl pyrrolidone and poloxamer NPs [51], dextran and poly(-lactide-co-glycolide) [DexPLGA] NPs [52]. Overall, these studies showed the importance of systematic formulation design to overcome poor solubility of the drug. In comparison with free Sorafenib, the majority of the reported Sorafenib NP formulations exhibited a significant increase in the retention time, a higher drug concentration in tumor tissues and an increased efficacy in inhibiting tumor growth.
Even more interesting results have been obtained with design, synthesis and biological evaluation of targeted Sorafenib nanoformulations. Wang et al. [53] prepared PSi nanoparticles functionalized with a specific peptide able to direct Sorafenib to the tumor tissue and thus enhance the cellular uptake and drug delivery efficiency. In detail, the targeting peptides were obtained by azide alkyne cycloaddition click reaction, an important tool for surface modification of nanomaterials. The new Sorafenib-loaded targeted NPs efficiently delivered the drug into the cells, resulting in enhanced in vitro antiproliferative activity, and should represent an interesting system for targeted cancer therapy.
Hong et al. [54] developed CXCR4-targeted NPs specific for activated HSCs in fibrotic livers. CXCR4 is a chemokine receptor induced in HSCs by various cellular stresses during the progression of liver fibrosis. As Sorafenib treatment could attenuate liver fibrosis and was associated with the inhibition of angiogenesis, the authors examined the anti-angiogenic activity of Sorafenib and Selumetinib (a MEK inhibitor) co-formulated in peptide-modified NPs (constituting PLGA, dipalmitoyl phosphatidylcholine, peptides (CTCE9908) and PEG). In mice with CCl4-induced liver fibrosis, treatment with Sorafenib/Selumetinib-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis and liver metastasis [55][56].
Other polymeric or targeted NPs have been recently reported for the treatment of HCC. As an example, Yu et al. [57] designed and synthesized bovine serum albumin (BSA)-coated zinc phthalocyanine (ZnPc) and Sorafenib NPs (ZnPc/SFB/BSA) able to trigger photodynamic therapy (PDT), photothermal therapy and chemotherapy. Upon irradiation at 730 nm, these NPs significantly suppressed HCC cell proliferation and metastasis and promoted in vitro cell apoptosis, with low toxicity and adequate blood compatibility. In addition, injection of ZnPc/SFB/BSA reduced tumor growth in a xenograft HCC model. All these results confirm that this type of nanoformulation could represent a promising strategy for HCC patients.
Recently, Li et al. [58] developed new Sorafenib-loaded dendritic polymeric NPs with excellent stability, high cellular uptake efficiency in HepG2 human liver cells and higher cytotoxicity than free Sorafenib. Furthermore, this NP formulation inhibited tumor growth in mice bearing HepG2 xenografts, with negligible side effects, thus representing a novel approach for enhanced therapy of HCC.
Sorafenib-loaded polymeric NPs (constituted by TPGS-b-PCL copolymer) were synthesized from ε-caprolactone and D-α-tocopheryl polyethylene glycol 1000 succinate via ring-opening polymerization. The obtained NPs contained Pluronic P123 modified with anti-GPC3 antibody (NP-SFB-Ab) and displayed good stability, high drug release into cell culture medium and improved cytotoxicity in comparison with non-targeted NP-Sorafenib and the free drug. In addition, these targeted NPs significantly inhibited the growth of HepG2 xenograft tumors in nude mice without producing side effects. These findings suggest NP-SFB-Ab as a promising new method for achieving targeted therapy in HCC [59].
The association of Sorafenib with other different therapeutic agents has also been investigated for HCC treatment. Cao et al. [60] reported the co-delivery of Sorafenib and curcumin by directed self-assembled NPs. This nanosystem was prepared taking advantage of the hydrophobic interactions among Sorafenib, curcumin and the hydrophobic segments of PEG derivatives of vitamin E succinate. This innovative nanoformulation showed in vitro cytotoxicity and cell apoptosis in BEL-7402 and Hep G2 cells, in addition to a good antiangiogenetic action.
Zhang et al. [61] reported Paclitaxel- and Sorafenib-loaded albumin nanoparticles to avoid taxol toxicities and to evaluate the anticancer efficacy of this combination. Interestingly, the authors obtained lower myelosuppression and hemolysis and an increased antitumor effect in animal models.
The co-delivery of plantamajoside (natural herbal medicines with excellent antiproliferative effect against many drug-resistant cancers) and Sorafenib by multi-functional PLA NPs was investigated to overcome drug resistance in HCC. NPs were produced and co-loaded with Sorafenib and plantamajoside and decorated with a polypeptide which specifically binds to biomolecules overexpressed on the surface of cancer cells. The authors demonstrated that this functionalization improved drug accumulation and penetration at tumor sites, resulting in a strong inhibition of tumor growth [62]. Li et al. [63] formulated a dual-targeting delivery system for enhanced HCC therapy by encapsulating Sorafenib and anti-miRNA21 (an antisense oligonucleotide with great potential in cancer therapy) in pentapeptide-modified reconstituted high-density lipoprotein NPs. In addition, these NPs expressed apolipoprotein A-I (ApoA-I) which specifically binds to overexpressed scavenger type B1 receptor (SR-B1) present in HCC parenchyma. This nanosystem was able to drive loaded drugs simultaneously to tumor neovascular and parenchyma, achieving precise delivery of therapeutics to maximize the efficacy. At the targeted sites, anti-miRNA21 would assist Sorafenib to exert powerful anticancer and anti-angiogenetic effects. The obtained results evidence that this chemo-gene system significantly increased Sorafenib action with negligible toxicity and reversed drug resistance, with improved efficacy in HCC [64].
Other nanoformulations have been developed to target different solid tumors, such as renal cell carcinoma (RCC). Liu et al. [65] prepared different Sorafenib-loaded PLGA, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes, and hydrophobically modified chitosan-coated DPPC liposomes with good action against RCC 786-0 renal cancer cells. Poojari et al. [66] assembled layer-by-layer (LbL) polyelectrolytes dextran-sulfate/poly-L-arginine with Sorafenib-encapsulated calcium carbonate NPs for oral cancer therapy. This innovative nanoformulation exhibited more potent antiproliferative, apoptotic and antimigratory activities in KB cells than the free drug, providing new insights for oral cancer therapy.

References

  1. Robertson, S.C.; Tynan, J.; Donoghue, D.J. RTK mutations and human syndromes: When good receptors turn bad. Trends Genet. 2000, 16, 265–271.
  2. Moradpour, Z.; Barghi, L. Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors. J. Pharm. Pharm. Sci. 2019, 22, 37–48.
  3. Yin, Y.; Yuan, X.; Gao, H.; Yang, Q. Nanoformulations of small molecule protein tyrosine kinases inhibitors potentiate targeted cancer therapy. Int. J. Pharm. 2020, 573, 118785.
  4. Druker, B.J.; Lydon, N.B. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic mye-logenous leukemia. J. Clin. Investig. 2000, 15, 3–7.
  5. Pisters, P.W.; Patel, S.R. Gastrointestinal stromal tumors: Current management. J. Surg. Oncol. 2010, 102, 530–538.
  6. Cheah, C.Y.; Burbury, K.; Apperley, J.F.; Huguet, F.; Pitini, V.; Gardembas, M.; Ross, D.M.; Forrest, D.; Genet, P.; Rousselot, P.; et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood 2014, 123, 3574–3577.
  7. Eilers, G.; Czaplinski, J.T.; Mayeda, M.; Bahri, N.; Tao, D.; Zhu, M.; Hornick, J.; Lindeman, N.I.; Sicinska, E.; Wagner, A.J.; et al. CDKN2A/p16 Loss Implicates CDK4 as a Therapeutic Target in Imatinib-Resistant Dermatofibrosarcoma Protuberans. Mol. Cancer Ther. 2015, 14, 1346–1353.
  8. Schenone, S.; Brullo, C.; Musumeci, F.; Botta, M. Novel dual Src/Abl inhibitors for hematologic and solid malignancies. Expert Opin. Investig. Drugs 2010, 19, 931–945.
  9. Hantschel, O.; Rix, U.; Schmidt, U.; Bürckstümmer, T.; Kneidinger, M.; Schütze, G.; Colinge, J.; Bennett, K.L.; Ellmeier, W.; Valent, P.; et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc. Natl. Acad. Sci. USA 2007, 104, 13283–13288.
  10. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angio-genesis. Cancer Res. 2004, 64, 7099–7109.
  11. Jain, L.; Woo, S.; Gardner, E.R.; Dahut, W.L.; Kohn, E.C.; Kummar, S.; Mould, D.R.; Giaccone, G.; Yarchoan, R.; Venitz, J.; et al. Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br. J. Clin. Pharmacol. 2011, 72, 294–305.
  12. Duncan, J.S.; Whittle, M.C.; Nakamura, K.; Abell, A.N.; Midland, A.A.; Zawistowski, J.S.; Johnson, N.L.; Granger, D.A.; Jordan, N.V.; Darr, D.B.; et al. Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer. Cell 2012, 149, 307–321.
  13. Abdelgalil, A.A.; Alkahtani, H.M.; Al-Jenoobi, F.I. Sorafenib. In Profiles of Drug Substances, Excipients and Related Methodology; Academic Press: New York, NY, USA, 2019; Volume 44, pp. 239–266.
  14. Boland, P.; Wu, J. Systemic therapy for hepatocellular carcinoma: Beyond sorafenib. Chin. Clin. Oncol. 2018, 7, 50.
  15. Tan, F.H.; Putoczki, T.L.; Stylli, S.S.; Luwor, R.B. Ponatinib: A novel multi-tyrosine kinase inhibitor against human ma-lignancies. OncoTargets Ther. 2019, 12, 635–645.
  16. Wylie, A.A.; Schoepfer, J.; Jahnke, W.; Cowan-Jacob, S.W.; Loo, A.; Furet, P.; Marzinzik, A.L.; Pelle, X.; Donovan, J.; Zhu, W.; et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature 2017, 543, 733–737.
  17. Hughes, T.P.; Mauro, M.J.; Cortes, J.E.; Minami, H.; Rea, D.; DeAngelo, D.J.; Breccia, M.; Goh, Y.T.; Talpaz, M.; Hoch-haus, A.; et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibi-tor Failure. N. Engl. J. Med. 2019, 381, 2315–2326.
  18. Schoepfer, J.; Jahnke, W.; Berellini, G.; Buonamici, S.; Cotesta, S.; Cowan-Jacob, S.W.; Dodd, S.; Drueckes, P.; Fabbro, D.; Gabriel, T.; et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J. Med. Chem. 2018, 61, 8120–8135.
  19. Zhang, L.; Li, M.; Yanli, Z.; Huanling, Z.; Jiuwei, C.; Aining, S.; Yu, H.; Jie, J.; Hao, J.; Xi, Z.; et al. Frontline flumatinib versus imatinib in patients with chronic myeloid leukemia in chronic phase: Results from the China randomized phase III study. J. Clin. Oncol. 2019, 37, 7004.
  20. Goldman, A.; Kulkarni, A.; Kohandel, M.; Pandey, P.; Rao, P.; Natarajan, S.K.; Sabbisetti, V.; Sengupta, S. Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer. ACS Nano 2016, 10, 5823–5834.
  21. Onda, T.; Masuda, A.; Yamakawa, K.; Tomiyama, C.; Yoneta, Y.; Akatsu, Y.; Yamamoto, K.; Mochizuki, A.; Inventors; Nippon Kayaku Co Ltd. Block Copolymer Conjugate of Physiologically Active Substance. United States Patent US 10,357,573, 23 July 2019.
  22. Dravid, V.P.; Nandwana, V.; Inventors; Northwestern University Assignee. Nanoparticle-Lipid Composite Carriers and Uses Thereof. United States Patent Application US 16/615,260, 4 June 2020.
  23. Xu, H.; Ji, H.; Li, Z.; Qiao, W.; Wang, C.; Tang, J. In vivo Pharmacokinetics and in vitro Release of Imatinib Mesylate-Loaded Liposomes for Pulmonary Delivery. Int. J. Nanomed. 2021, 16, 1221–1229.
  24. Soundararajan, R.; Wang, G.; Petkova, A.; Uchegbu, I.F.; Schätzlein, A.G. Hyaluronidase Coated Molecular Envelope Technology Nanoparticles Enhance Drug Absorption via the Subcutaneous Route. Mol. Pharm. 2020, 17, 2599–2611.
  25. Gao, J.; Qiao, Z.; Liu, S.; Xu, J.; Wang, S.; Yang, X.; Wang, X.; Tang, R. Preparation of small molecule prodrug composed of pH-sensitive orthoester and dasatinib conjugate. Eur. J. Pharm. Biopharm. 2021, 163, 188–197.
  26. Horner, G.; Rai, P.; Agrawal, S.; Parker, B. Remotely Triggered Therapy. United States Patent Application US 17/000,205, 17 December 2020.
  27. Tran, D.; Le, S.B. Methods for Targeted Treatment and Prediction of Patient Survival in Cancer. PCT Int. Appl. WO 2020163639 A1 20200813, 13 August 2020.
  28. Zhang, L.; Wang, S.; Zhang, M.; Sun, J. Nanocarriers for oral drug delivery. J. Drug Target. 2013, 21, 515–527.
  29. Chauhan, R.; Balgemann, R.; Greb, C.; Nunn, B.M.; Ueda, S.; Noma, H.; McDonald, K.; Kaplan, H.J.; Tamiya, S.; O’Toole, M.G. Production of dasatinib encapsulated spray-dried poly (lactic-co-glycolic acid) particles. J. Drug Deliv. Sci. Technol. 2019, 53, 101204.
  30. Li, Q.; Lai, K.L.; Chan, P.S.; Leung, S.C.; Li, H.Y.; Fang, Y.; To, K.; Choi, C.H.J.; Gao, Q.Y.; Lee, T.W. Micellar delivery of dasatinib for the inhibition of pathologic cellular processes of the retinal pigment epithelium. Colloids Surf. B Biointerfaces 2016, 140, 278–286.
  31. Cai, L.; Zhou, H.; Liu, L.; He, H.; Liang, R. Preparation Method and Application of Nanoparticle Drug-Carrying System. Faming Zhuanli Shenqing CN 110859817, 6 March 2020.
  32. McKeon, F.; Duleba, M.; Zhang, Y.; Xie, J.; Xian, W.; Vincent, M. Screening Methods for Identifying Therapeutic Agents for Treating Chronic Inflammatory Injury, Metaplasia, Dysplasia and Cancers of Epithelial Tissues. PCT Int. Appl. WO 2020219963, 29 November 2020.
  33. Koehl, N.J.; Griffin, B.T.; Holm, R.; Holm, R.; Kuentz, M. Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats. Pharm. Res. 2020, 37, 124.
  34. Jesson, G.; Brisander, M.; Andersson, P.; Demirbueker, M.; Derand, H.; Lennernaes, H.; Malmsten, M. Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors. Pharm. Res. 2014, 31, 694–705.
  35. Fan, Q.-Q.; Zhang, C.-L.; Qiao, J.-B.; Cui, P.-F.; Xing, L.; Oh, Y.-K.; Jiang, H.-L. Extracellular matrix-penetrating nanodrill micelles for liver fibrosis therapy. Biomaterials 2020, 230, 119616.
  36. Cortese, B.; D’Amone, S.; Palamà, I.E. Wool-Like Hollow Polymeric Nanoparticles for CML Chemo-Combinatorial Therapy. Pharmaceutics 2018, 10, 52.
  37. Robinson, W.H.; Postolova, A.; Raghu, H. Tyrosine Kinase Inhibitor Formulations for the Treatment of Mast Cell-Mediated Inflammatory Diseases and Methods of Use Thereof. United States Patent Application US 20170312282, 2 November 2017.
  38. Zhang, Y.; Zhang, H.; Peng, R. Preparation and in vitro release of ponatinib nanosuspensions. Guangdong Yaoxueyuan Xuebao 2014, 30, 544–548.
  39. Zinger, A.; Baudo, G.; Naoi, T.; Giordano, F.; Lenna, S.; Massaro, M.; Ewing, A.; Kim, H.R.; Tasciotti, E.; Yustein, J.T.; et al. Reproducible and Characterized Method for Ponatinib Encapsulation into Biomimetic Lipid Nanoparticles as a Platform for Multi-Tyrosine Kinase-Targeted Therapy. ACS Appl. Bio Mater. 2020, 3, 6737–6745.
  40. Kallus, S.; Englinger, B.; Senkiv, J.; Laemmerer, A.; Heffeter, P.; Berger, W.; Kowol, C.R.; Keppler, B.K. Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index. Nanomedicine 2018, 14, 2632–2643.
  41. Zhang, J.; Tao, C.; Song, X.; Li, W. Preparation Method of Injectable Sunitinib Nanoparticle. Faming Zhuanli Shenqing CN 108030927, 15 May 2018.
  42. Otroj, M.; Taymouri, S.; Varshosaz, J.; Mirian, M. Preparation and characterization of dry powder containing sunitinib loaded PHBV nanoparticles for enhanced pulmonary deliver. J. Drug Deliv. Sci. Technol. 2020, 56, 101570.
  43. Joseph, J.J.; Sangeetha, D.; Gomathi, T. Sunitinib loaded chitosan nanoparticles formulation and its evaluation. Int. J. Biol. Macromol. 2016, 82, 952–958.
  44. Shi, J.; Ju, R.; Sun, M.; Li, X.; Zhao, Y.; Zeng, F.; Lu, W. Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG2000-pemetrexed conjugate and the inhibitory effect to resistant breast cancer in vitro. J. Chin. Pharm. Sci. 2014, 23, 287–294.
  45. Shi, J.; Sun, M.; Li, X.; Zhao, Y.; Ju, R.; Mu, L.; Yan, Y.; Li, X.; Zeng, F.; Lu, W. A combination of targeted sunitinib lipo-somes and targeted vinorelbine liposomes for treating invasive breast cancer. J. Biomed. Nanotechnol. 2015, 11, 1568–1582.
  46. Bhatt, P.; Narvekar, P.; Lalani, R.; Chougule, M.B.; Pathak, Y.; Sutariya, V. An in vitro Assessment of Thermo-Reversible Gel Formulation Containing Sunitinib Nanoparticles for Neovascular Age-Related Macular Degeneration. AAPS PharmSciTech 2019, 20, 1–14.
  47. Zhang, H.; Zhang, F.; Yan, S. Preparation, in vitro release, and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles. Int. J. Nanomed. 2012, 7, 2901–2910.
  48. Xu, X.; Tang, X.; Wu, X.; Feng, X. Biosynthesis of sorafenib coated graphene nanosheets for the treatment of gastric cancer in patients in nursing care. J. Photochem. Photobiol. B Biol. 2019, 191, 1–5.
  49. Almeida, P.V.; Shahbazi, M.; Correia, A.; Maekilae, E.; Kemell, M.; Salonen, J.; Hirvonen, J.; Santos, H. A multifunctional nanocomplex for enhanced cell uptake, endosomal escape and improved cancer therapeutic effect. Nanomedicine 2017, 12, 1401–1420.
  50. Sheng, X.; Huang, T.; Qin, J.; Li, Q.; Wang, W.; Deng, L.; Dong, A. Preparation, pharmacokinetics, tissue distribution and antitumor effect of sorafenib-incorporating nanoparticles in vivo. Oncol. Lett. 2017, 14, 6163–6169.
  51. Park, S.Y.; Kang, Z.; Thapa, P.; Jin, Y.S.; Park, J.W.; Lim, H.J.; Lee, J.Y.; Lee, S.; Seo, M.; Kim, M.; et al. Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach. Intern. J. Pharm. 2019, 566, 229–238.
  52. Kim, D.H.; Kim, M.-D.; Choi, C.-W.; Chung, C.-W.; Ha, S.H.; Kim, C.H.; Shim, Y.-H.; Jeong, Y.-I.; Kang, D.H. Antitumor activity of sorafenib-incorporated nanoparticles of dextran/poly(dl-lactide-co-glycolide) block copolymer. Nanoscale Res. Lett. 2012, 7, 91.
  53. Wang, C.-F.; Mäkilä, E.M.; Kaasalainen, M.H.; Liu, D.; Sarparanta, M.; Airaksinen, A.J.; Salonen, J.J.; Hirvonen, J.T.; Santos, H.A. Copper-free azide–alkyne cycloaddition of targeting peptides to porous silicon nanoparticles for intracellular drug uptake. Biomaterials 2014, 35, 1257–1266.
  54. Hong, F.; Tuyama, A.; Lee, T.F.; Loke, J.; Agarwal, R.; Cheng, X.; Garg, A.; Fiel, M.I.; Schwartz, M.; Walewski, J.; et al. Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activation. Hepatology 2009, 49, 2055–2067.
  55. Sung, Y.-C.; Liu, Y.-C.; Chao, P.-H.; Chang, C.-C.; Jin, P.-R.; Lin, T.-T.; Lin, J.-A.; Cheng, H.-T.; Wang, J.; Lai, C.P.; et al. Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development. Theranostics 2018, 8, 894–905.
  56. Chen, Y.; Liu, Y.C.; Sung, Y.C.; Ramjiawan, R.R.; Lin, T.T.; Chang, C.C.; Jeng, K.S.; Chang, C.F.; Liu, C.H.; Gao, D.Y.; et al. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Sci. Rep. 2017, 7, 44123.
  57. Yu, X.-N.; Deng, Y.; Zhang, G.-C.; Liu, J.; Liu, T.-T.; Dong, L.; Zhu, C.-F.; Shen, X.-Z.; Li, Y.-H.; Zhu, J.-M. Sorafenib-Conjugated Zinc Phthalocyanine Based Nanocapsule for Trimodal Therapy in an Orthotopic Hepatocellular Carcinoma Xenograft Mouse Model. ACS Appl. Mater. Interfaces 2020, 12, 17193–17206.
  58. Li, Z.; Ye, L.; Liu, J.; Lian, D.; Li, X. Sorafenib-loaded nanoparticles based on biodegradable dendritic polymers for enhanced therapy of hepatocellular carcinoma. Intern. J. Nanomed. 2020, 15, 1469–1480.
  59. Tang, X.; Chen, L.; Li, A.; Cai, S.; Zhang, Y.; Liu, X.; Jiang, Z.; Liu, X.; Liang, Y.; Ma, D. Anti-GPC3 antibody-modified sorafenib-loaded nanoparticles significantly inhibited HepG2 hepatocellular carcinoma. Drug Deliv. 2018, 25, 1484–1494.
  60. Cao, H.; Wang, Y.; He, X.; Zhang, Z.; Yin, Q.; Chen, Y.; Yu, H.; Huang, Y.; Chen, L.; Xu, M.; et al. Codelivery of Sorafenib and Curcumin by Directed Self-Assembled Nanoparticles Enhances Therapeutic Effect on Hepatocellular Carcinoma. Mol. Pharm. 2015, 12, 922–931.
  61. Zhang, J.; He, B.; Qu, W.; Cui, Z.; Wang, Y.; Zhang, H.; Wang, J.; Zhang, Q. Preparation of the albumin nanoparticle system loaded with both paclitaxel and sorafenib and its evaluation in vitro and in vivo. J. Microencapsul. 2011, 28, 528–536.
  62. Zan, Y.; Dai, Z.; Liang, L.; Deng, Y.; Dong, L. Co-delivery of plantamajoside and sorafenib by a multi-functional nano-particle to combat the drug resistance of hepatocellular carcinoma through reprograming the tumor hypoxic microenvironment. Drug Deliv. 2019, 26, 1080–1091.
  63. Li, Z.; Rana, T.M. Therapeutic targeting of microRNAs: Current status and future challenges. Nat. Rev. Drug Discov. 2014, 13, 622–638.
  64. Li, M.; Su, Y.; Zhang, F.; Chen, K.; Xu, X.; Xu, L.; Zhou, J.; Wang, W. A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy. Acta Biomater. 2018, 75, 413–426.
  65. Liu, J.; Boonkaew, B.; Arora, J.; Mandava, S.H.; Maddox, M.M.; Chava, S.; Callaghan, C.; He, J.; Dash, S.; John, V.T.; et al. Comparison of Sorafenib-Loaded Poly (Lactic/Glycolic) Acid and DPPC Liposome Nanoparticles in the in Vitro Treatment of Renal Cell Carcinoma. J. Pharm. Sci. 2015, 104, 1187–1196.
  66. Poojari, R.; Kini, S.; Srivastava, R.; Panda, D. Intracellular interactions of electrostatically mediated layer-by-layer assembled polyelectrolytes based sorafenib nanoparticles in oral cancer cells. Colloids Surf. B Biointerfaces 2016, 143, 131–138.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Eleonora Russo
View Times: 568
Revisions: 2 times (View History)
Update Date: 22 Jun 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback