Nanomedicine therapeutic approaches to overcome cancer drug resistance

“from normal stem cells versus progenitor cells, is still not clear and may vary from tumor to tumor or by tumor type [48].”

“Tumor initiating cells were later isolated in breast carcinomas, and it was shown that only a subset of cells could be serially passaged and gave rise to both phenotypically identical and diverse cells consistent with those found in the initial tumor [40].”

“Additional stem cell markers including CD44 [38,121] and CD133 [121] have been associated with drug resistance and may serve as potential targets for future nanodrugs to eliminate CSCs and prevent recurrence.”

“Inframe deletions in exon 19 and single missense mutations account for approximately 90% of the EGFR mutations, and result in an increased sensitivity to both small molecule inhibitors, gefitinib and erlotinib [52-54].”

“It is accepted at the current stage of cancer biology that tumors at the same clinical grade and histological status are genetically heterogeneous and contain subclonal populations [33].”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“showed that only a very small subset of cells that were CD34+CD38− had the ability to cause AML in NOD/SCID mice, indicating that subpopulations of cells had differential abilities to proliferate and transfer disease [39].”

“3 [28].”

“Advances to liposome design have also been made with the addition of polyethylene glycol (PEG, known as stealth liposomes), which increases circulation time, as well as strategies for a triggered release of the drug once internalized, such as hyperthermia, as is used in ThermoDox®, which is currently in Phase III tria…”

“Inframe deletions in exon 19 and single missense mutations account for approximately 90% of the EGFR mutations, and result in an increased sensitivity to both small molecule inhibitors, gefitinib and erlotinib [52-54].”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“However, acquired resistance to therapy is associated with a secondary mutation in exon 20 that leads to substitution of methionine for threonine at position 790M (T790M) in the kinase domain, preventing the binding of erlotinib [57].”

“4B [49].”

“However, it is important to note that there are still possible negative side effects including an immunological response through complement activation, toxicity of side products, and possible accumulation of PEG due to its non-biodegradability [94].”

“Further, the resistance was not found to be associated with KRAS mutations that can cause primary resistance and transfection of cells in vitro conferred resistance to gefitinib and erlotinib in normally sensitive cells [58].”

“Additional stem cell markers including CD44 [38,121] and CD133 [121] have been associated with drug resistance andmay serve as potential targets for future nanodrugs to eliminate CSCs and prevent recurrence.”

“Cancer stem cells, also known as tumor initiating cells, are cells that have the capacity to self-renew and to give rise to the heterogeneous lineages that are found within a tumor [35].”

“For water-soluble polymers, drugs can be covalently bound to increase circulation time and limit toxicity to normal tissues [6-9].”

“[132,147]”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“The pH of the tumor microenvironment can also influence the effectiveness of cytotoxic drugs and may inhibit the active transport of some therapeutics [61,64].”

“In addition, hypoxia can lead to the activation of genes associated with angiogenesis, survival, and glycolysis through the transcription factor hypoxia-inducible factor 1 (HIF-1) and may contribute to a drug-resistant phenotype [61,72].”

“The first discovery was the mdr 1 gene that encodes the high molecular weight P-glycoprotein (P-gp/ABCB1), which is amplified in drug-resistant cells and leads to a decrease in drug accumulation [19].”

“This was confirmed 6 years later in humans when only 1 in 1,000 to 1 in 5,000 lung cancer, ovarian cancer, or neuroblastoma cells formed colonies in soft agar [37].”

“These mechanisms are used to prevent the transmission of damaged DNA and to avoid malignant transformation [29].”

“Currently, the available clinical data relate to passively targeted liposomes, but a number of actively targeting nanoparticles are also in clinical development [79].”

“For the treated patients that did exhibit subclonal evolution, the somatic driver mutations that expanded were detectable at the first time point and thus could potentially be anticipated in association with treatment [34].”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“Further, these tumors have dysfunctional lymphatic drainage, which also results in drug accumulation [78].”

“These areas result from abnormal angiogenesis or from the compression/closing of blood vessels by cancer cells [70].”

“Cancer stem cells have also been isolated from medulloblastoma, glioblastoma [41], ependymoma [42], colon cancer [43,44], chronic and acute myeloid leukemia [45], pancreatic cancer [46], and head and neck squamous cell carcinomas [47].”

“Somatic mutations resulting in a gain-of-function activation of the tyrosine kinase domain of EGFR in a cohort of non-small cell lung cancer (NSCLC) were discovered in 35% of the enrolled patients and were shown to significantly impact response rates to gefitinib (55%) [51].”

“These therapeutic antibodies, as well as targeting antibodies such as 2C5 [2] and anti-transferrin receptor mAbs [99-101], can be conjugated to various nanoparticles to improve efficacy and increase binding affinity to the cancer cells.”

“Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville MP, Bours V. NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells.”

“Currently, one phase I clinical trial using tumor necrosis factor α (TNFα) bound to colloidal gold is ongoing to treat advanced solid tumors such as sarcomas and melanomas [14].”

“Further, covalent attachment of hydrophobic drugs such as Doxorubicin and Paclitaxel is frequently employed [6,7,10].”

“Thus, the blockage of cancer specific extracellular matrix protein synthesis may lead to physiological normalization of tumor tissue structure (vascular supply) and potential reduction of resistance to conventional chemotherapy [76,77].”

“These hypoxic cells often revert to aerobic metabolism for the production of ATP (the Warburg effect) [73,74] to maintain enough energy to continue to thrive.”

“Nearly 70% of patients with a mutation (found in 10-25% of all NSCLC patients) respond to therapy compared to only a 10% response rate when no mutations are present [55,56].”

“Further, the anti-apoptotic, pro-survival regulator Bcl-2 [31] and nuclear factor kappa B (NF-κB), a transcription factor that controls genes that suppress apoptotic responses [32], are frequently overexpressed in cancer cells and lead to increased survival.”

“Sodium citrate can also be used as a reducing agent for gold formation, and a stabilizer to avoid aggregation during synthesis [13].”

“Small molecules attached to peptides can be internalized through this mechanism, whereas TAT-polymer conjugate can be taken up through energy-dependent endocytosis or macropinocytosis [18].”

“Interestingly, it does not affect the binding ability of a different anti-EGFR mAb, panitumumab [59].”

“Another group encapsulated curcumin, known as P-glycoprotein pump inhibitor, and Paclitaxel in a nanoemulsion of flaxseed oil to effectively treat wild-type and drug resistant SKOV3 ovarian tumor cells [115].”

“Further, tumor microenvironment can create hypoxic situations in which tumor tissue has a diminished oxygen supply that can contribute to MDR [69].”

“Antagonists of CXCR4 can disrupt these interactions, forcing the leukemia cells back into circulation where they are more susceptible to chemotherapeutic drugs [122], and may serve as crucial additions on nanodrugs.”

“These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy [75]”

“stem cells [135,145]”

“Further, the anti-apoptotic, pro-survival regulator Bcl-2 [31] and nuclear factor kappa B (NF-κB), a transcription factor that controls genes that suppress apoptotic responses [32], are frequently overexpressed in cancer cells and lead to increased survival.”

“Further, these peptides may not only play a role in homing but in tumor-penetration, as is the case with iRGD, because they allow for the exit from blood vessels and can activate a tissue-specific transport pathway [105], which is a big advantage in treating resistant tumors.”

“Cell cycle arrest does not occur when mutations, chromosomal rearrangements, and epigenetic changes are present, even when induced by anticancer therapies that induce DNA damage to cause cytotoxicity [30].”

“Regression of tumors was apparent in xenograft models of human ovarian tumor drug-resistant A2780/AD, human breast tumor MCF-7, human lung tumor A549, and human epidermoid tumor KB using this drug as a non-specific targeting agent [109].”

“presently understood due to the acute in vivo toxicity [15].”

“Further, liposomal anti-MRP-1 and anti-Bcl2 siRNA in combination with Doxorubicin were used to suppress pump and non-pump mediated cellular resistance and to cause death in MDR lung cancer cells [116].”

“Weakly acidic drugs, such as cyclophosphamide, tend to concentrate in neutral extracellular space [66].”

“With repeated treatment, tumors often become resistant not only to the specific chemotherapeutic agent being employed, but cross-resistant to both similar and structurally unrelated classes of cytotoxic drugs [16-18].”

“a binding motif for integrins, such as αvβ3, which is specifically expressed on tumor endothelia [104], and those that have a form of aminopeptidase N (CD13) that binds peptides with the NGR motif.”

“Current approaches to nanotubes include the incorporation of drugs such as Doxorubicin and Paclitaxel, nucleic acids including antisense oligonucleotides and short interfering RNAs (siRNAs), [12] and the use of nanotubes as contrast agents for imaging.”

“1 Antibodies and their fragments specifically target cancer cells—A number of mAbs have been approved for the treatment of various cancers including rituximab (Rituxan) for non-Hodgkin's lymphoma [95], the anti-HER2 trastuzumab (Herceptin) [96], the anti-VEGF bevacizumab (Avastin) to inhibit angiogenesis [97], and the…”

“The delivery of these liposomes to cancer cells often relies on passive targeting and is based on the enhanced permeability and retention (EPR) effect, for which a leaky tumor vasculature is necessary [1].”

“diacrylate-β-tetraethylenepentamine]-polycaprolactone copolymer [131] for the inhibition of efflux-dependent mechanisms or carbon nanotubes for membrane permeabilization and sensitization to photo thermal therapy [132].”

“Active cargo, such as siRNA, and antibodies specifically inhibit synthesis or function of proteins, which are key players in resistance mechanisms [134,135,137].”

“However, once inside the cell, these nanoparticles may either fuse with lysosomes or be recycled back to the cell surface, making endosome escape a key limitation [107].”

“Tang QL, Zhao ZQ, Li JC, Liang Y, Yin JQ, Zou CY, Xie XB, Zeng YX, Shen JN, Kang T, Wang J. Salinomycin inhibits osteosarcoma by targeting its tumor stem cells.”

“Thirteen of the 48 known ABC transporters contribute to MDR [16].”

“Thus, weakly basic drugs, such as Doxorubicin, are protonated and have reduced cellular uptake [65].”

“Further, covalent attachment of hydrophobic drugs such as Doxorubicin and Paclitaxel is frequently employed [6,7,10].”

“Currently, all nanoparticles using aptamers as target agents are still in the preclinical phase [103].”

“Rapid endosomal escape was confirmed using confocal laser scanning microscopy, and ~80% VEGF mRNA knockdown in pancreatic cancer cells was achieved [108].”

“5 (the range of acidification in late endosomes and lysosomes), activity was upregulated and membrane disruption allowed for endosomal escape of the nanoconjugate [76].”

“Further, covalent attachment of hydrophobic drugs such as Doxorubicin and Paclitaxel is frequently employed [6,7,10].”

“The adhesion leads to a G1 arrest associated with increased p27kip1 expression and inhibition of cyclin A and E kinase activity; disruption of this interaction returns the tumor cells to a drug-sensitive state [62].”

“A study of osteosarcoma cell lines showed that an anti-cancer drug Salinomycin could suppress tumor cells in vitro and in vivo by targeting CSC, potentially through the Wnt/β-catenin signaling pathway [119].”

“Other proteins including multidrug resistance proteins (MRPs/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are also upregulated in cancer cells and effectively remove cytotoxic agents including Doxorubicin [20-23] and Paclitaxel [24-27] greatly decreasing their concentration within tumor cells, as shown in F…”

“The first PEGylated nanoparticle approved in the United States and Europe is liposomal Doxorubicin (Doxil®/Caelyx® [PLD]) for the treatment of Kaposi's sarcoma [85], recurrent ovarian cancer [86] and multiple myeloma [87], with additional clinical trials ongoing for metastatic breast [88], and hormone refractory prost…”

“The conjugation of PEG to liposomes [1,90], polymer-based nanoparticles and micelles [7,91], dendrimers [92], gold nanoparticles [11,13], and superparamagnetic iron oxide [93] is now a common practice to improve circulation time and avoid clearance.”

“The first PEGylated nanoparticle approved in the United States and Europe is liposomal Doxorubicin (Doxil®/Caelyx® [PLD]) for the treatment of Kaposi's sarcoma [85], recurrent ovarian cancer [86] and multiple myeloma [87], with additional clinical trials ongoing for metastatic breast [88], and hormone refractory prost…”

“The micelle core then disintegrates in the early endosomal pH of the cells to release Doxorubicin.”

“Multiple clinical trials are ongoing using amphiphilic diblock copolymer forming micelles to deliver Paclitaxel to treat breast, non-small cell lung cancer, and advanced pancreatic cancer [11].”

“diacrylate-β-tetraethylenepentamine]-polycaprolactone copolymer [131] for the inhibition of efflux-dependent mechanisms or carbon nanotubes for membrane permeabilization and sensitization to photo thermal therapy [132].”

“The conjugation of PEG to liposomes [1,90], polymer-based nanoparticles and micelles [7,91], dendrimers [92], gold nanoparticles [11,13], and superparamagnetic iron oxide [93] is now a common practice to improve circulation time and avoid clearance.”

“These therapeutic antibodies, as well as targeting antibodies such as 2C5 [2] and anti-transferrin receptor mAbs [99-101], can be conjugated to various nanoparticles to improve efficacy and increase binding affinity to the cancer cells.”

“These hypoxic cells often revert to aerobic metabolism for the production of ATP (the Warburg effect) [73,74] to maintain enough energy to continue to thrive.”

“Other proteins including multidrug resistance proteins (MRPs/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are also upregulated in cancer cells and effectively remove cytotoxic agents including Doxorubicin [20-23] and Paclitaxel [24-27] greatly decreasing their concentration within tumor cells, as shown in F…”

“used a mathematical model combined with high throughput flow cytometry and quantitative confocal microscopy to confirm a general trend of reduced internalization by RES cells [84].”

“Drug distribution is also affected by the composition and organization of the extracellular matrix [67].”

“A number of liposomes with the addition of targeting ligands, such as the mAb 2C5 with Doxorubicin (Doxil®) [2] and an anti-HER2 mAb with Paclitaxel [3], are in the preclinical phase, whereas others are already undergoing clinical trials.”

“The conjugation of PEG to liposomes [1,90], polymer-based nanoparticles and micelles [7,91], dendrimers [92], gold nanoparticles [11,13], and superparamagnetic iron oxide [93] is now a common practice to improve circulation time and avoid clearance.”

“Other proteins including multidrug resistance proteins (MRPs/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are also upregulated in cancer cells and effectively remove cytotoxic agents including Doxorubicin [20-23] and Paclitaxel [24-27] greatly decreasing their concentration within tumor cells, as shown in F…”

“The knockdown of other CSC related pathways including tissue transglutaminase (TG2) by gene silencing using liposomal anti-TG2 siRNA combined with gemcitabine to treat Panc-28 pancreatic cancer cells was efficacious in reducing tumor growth and preventing metastasis [120].”

“The greater drug accumulation was due to the avoidance of the drug efflux pump mechanism via receptor-mediated endocytosis [111].”

“Another version of PMLA containing PEG, with Doxorubicin conjugated via pH-sensitive hydrazone linkage, was able to effectively inhibit growth of U251 more than Doxorubicin alone due to the modified drug uptake mechanism that evaded drug efflux pumps [112].”

“An initial response to anti-VEGF therapy often results in a hypoxia-triggered upregulation of non-VEGF angiogenic factors, such as those in the fibroblast growth factor (FGF) family, and a recurrence of angiogenesis [50].”

“1 Antibodies and their fragments specifically target cancer cells—A number of mAbs have been approved for the treatment of various cancers including rituximab (Rituxan) for non-Hodgkin's lymphoma [95], the anti-HER2 trastuzumab (Herceptin) [96], the anti-VEGF bevacizumab (Avastin) to inhibit angiogenesis [97], and the…”

“Drug efflux systems [129–131,133–136], resistance due to presence of CSC [132,137–139], DNA damage/repair [136,140–142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets f…”

“In vivo model Gold nanoparticles Multiple α-Bic- and β-Bic antiandrogens Multivalent binding to androgen receptor and to Gprotein coupled receptor (GPRC6A); The antiandrogens inhibit binding of androgen [143,146] Human breast MDA-MB-231 and MDA-MB-468 cell lines, and brain cancer cell lines U87MG and T98G In vitro mod…”

“Drug efflux systems [129–131,133–136], resistance due to presence of CSC [132,137–139], DNA damage/repair [136,140–142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets f…”

“oxide nanoparticle [139]”

“CSC resistance is achieved through increased Wnt/β-catenin and Notch signaling, high levels of ATP cassette reporters, altered DNA repair mechanisms, and slow proliferation rate [118].”

“For water-soluble polymers, drugs can be covalently bound to increase circulation time and limit toxicity to normal tissues [6-9].”

“Numerous modifications of these inhibitors have appeared as promising candidates, but clinical trials continue to fail [113].”

“Finally, stealth liposomes containing PSC 833 (Valspodar, a cyclosporin A analogue that is more effective) and Doxorubicin were able to reverse MDR in the Doxorubicin-resistant human breast cancer cell line T47D/TAMR-6 [117].”

“The conjugation of PEG to liposomes [1,90], polymer-based nanoparticles and micelles [7,91], dendrimers [92], gold nanoparticles [11,13], and superparamagnetic iron oxide [93] is now a common practice to improve circulation time and avoid clearance.”

“Delivery of TNFα using both RGD and NGR peptides has shown to decrease the effective dose by up to 1,000-fold [105] and an NGR-hTNF peptide is currently in phase III clinical trials [106].”

“Drug efflux systems [129–131,133–136], resistance due to presence of CSC [132,137–139], DNA damage/repair [136,140–142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets f…”

“Antisense oligonucleotides attached to polymalic acid biopolymer that block wild-type EGFR and mutated EGFRvIII receptor synthesis have been successfully used to treat triple negative breast cancer [60] employing a strategy based on acquired mutations by the MDA-MB-468 breast cancer cell line.”

“These therapeutic antibodies, as well as targeting antibodies such as 2C5 [2] and anti-transferrin receptor mAbs [99-101], can be conjugated to various nanoparticles to improve efficacy and increase binding affinity to the cancer cells.”

“Despite the fact that the EPR-based targeting is only passive and may be unpredictable, nanodrugs consistently have a better accumulation within a tumor than free drugs including Paclitaxel [80], rapamycin [81], thiostrepton [8], Doxorubicin [82], and Salinomycin [83], among countless others.”

“Nearly 70% of patients with a mutation (found in 10-25% of all NSCLC patients) respond to therapy compared to only a 10% response rate when no mutations are present [55,56].”

“Other proteins including multidrug resistance proteins (MRPs/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are also upregulated in cancer cells and effectively remove cytotoxic agents including Doxorubicin [20-23] and Paclitaxel [24-27] greatly decreasing their concentration within tumor cells, as shown in F…”

“Therefore, it is not only the inhibitory effect of the siRNA, but also the immunostimulatory effect of the treatment that leads to a reduction in tumor size [124].”

“Active cargo, such as siRNA, and antibodies specifically inhibit synthesis or function of proteins, which are key players in resistance mechanisms [134,135,137].”

“Drug efflux systems [129–131,133–136], resistance due to presence of CSC [132,137–139], DNA damage/repair [136,140–142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets f…”

“The micelle core then disintegrates in the early endosomal pH of the cells to release Doxorubicin.”

“resistance; PTX inhibition of cell division [138,144]”

“The first PEGylated nanoparticle approved in the United States and Europe is liposomal Doxorubicin (Doxil®/Caelyx® [PLD]) for the treatment of Kaposi's sarcoma [85], recurrent ovarian cancer [86] and multiple myeloma [87], with additional clinical trials ongoing for metastatic breast [88], and hormone refractory prost…”

“These therapeutic antibodies, as well as targeting antibodies such as 2C5 [2] and anti-transferrin receptor mAbs [99-101], can be conjugated to various nanoparticles to improve efficacy and increase binding affinity to the cancer cells.”

“The micelle core then disintegrates in the early endosomal pH of the cells to release Doxorubicin.”

“Antibodies and their fragments specifically target cancer cells A number of mAbs have been approved for the treatment of various cancers including rituximab (Rituxan) for non-Hodgkin's lymphoma [95], the anti-HER2 trastuzumab (Herceptin) [96], the anti-VEGF bevacizumab (Avastin) to inhibit angiogenesis [97], and the a…”

“The first PEGylated nanoparticle approved in the United States and Europe is liposomal Doxorubicin (Doxil®/Caelyx® [PLD]) for the treatment of Kaposi's sarcoma [85], recurrent ovarian cancer [86] and multiple myeloma [87], with additional clinical trials ongoing for metastatic breast [88], and hormone refractory prost…”

“Drug efflux systems [129–131,133–136], resistance due to presence of CSC [132,137–139], DNA damage/repair [136,140–142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets f…”

“To date, there has been limited success in overcoming drug resistance in cancers through the use of novel small molecule chemotherapeutics (5, 6), or nanoformulations of existing chemotherapeutics (7-9).”

“The primary rationale of using a suitable drug delivery system is its ability to ensure a higher and longer duration of drug bioavailability and thereby enhanced therapeutic efficacy.(14,15) Various materials with different structural forms are conjugated with drugs to prepare nano drug delivery systems.”