Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Figures & data

Table 1 Examples of using nanomedicines to overcome tumor cell resistance to representative drugs in different classes of cancer chemotherapeutics

Classes of cancer chemotherapeutics	Representative drugs	Common mechanisms of resistance	Example(s) of overcoming the resistance using nanomedicines	Comments	Reference
Alkylating agents	Temozolomide	The DNA repair enzyme MGMT, which repairs O^6-methylguanine adducts; Cells that are defective in MMR are generally resistant to temozolomide	Temozolomide nanoconjugates were synthesized using poly(β-l-malic acid), which comprised LLL and antibody to TfR. Temozolomide-resistant cells were sensitive to the temozolomide-nanoconjugates	The absorption of the temozolomide nanoconjugates was by receptor-mediated endocytosis. The conjugates may have increased the plasma half-life of temozolomide	^Citation58, ^Citation206
Antimetabolites	Methotrexate	Efflux transporters play a major role in methotrexate resistance	Methotrexate was conjugated to QDs and the resultant methotrexate-QDs were significantly more cytotoxic than free methotrexate in methotrexate-resistant KB cells	Methotrexate-QDs were effectively taken up by methotrexate-resistant KB cells, and the nanoconjugates were shown to evade efflux	^Citation71
	Cytarabine	Transmembrane efflux pumps, decreased hENT1 expression, dCK deficiency, increase of CDA expression	Squalenoyl–cytarabine conjugate–based NPs can overcome cytarabine resistance in L1210R cells both in vitro and in vivo	The NPs may have increased the intracellular level of cytarabine and reduced intracellular cytarabine deamination	^Citation207
Natural products	Docetaxel	Overexpression of P-gp/MDR1, increased expression of BCRP	Docetaxel loaded in PLGA-d-α-tocopheryl polyethylene glycol 1000 succinate/Poloxamer 235 nanoparticles was significantly more cytotoxic to docetaxel-resistant human breast adenocarcinoma MCF-7/TXT cells than docetaxel solution in culture and in a mouse model	NPs increased the uptake and reduced the efflux of docetaxel in MCF-7/TXT cells	^Citation74
	Doxorubicin	Overexpression of ABC transporters such as P-gp, alterations of drug target, modulation of programed cell death pathways	Doxorubicin encapsulated in mesoporous silica nanoparticles can overcome MCF-7/MDR1 cell resistance to doxorubicin	The mesoporous silica nanoparticles reduced doxorubicin efflux	^Citation79
Hormones and hormone antagonists	Tamoxifen	Altered ER expression, especially on the plasma membrane; altered expression of microRNAs; signaling pathways that regulate EMT in the tumor microenvironment	Tamoxifen-incorporated MnSOD siRNA nanoparticles were prepared. Tamoxifen-resistance of breast cancer cells was reversed when the antagonistic MnSOD activity was silenced by the MnSOD siRNA nanoparticles both in vitro and in vivo	The siRNA inhibited MnSOD activity	^Citation85
Miscellaneous agents	Canthaplatin, a prodrug of cisplatin	Reduced drug uptake, DNA repair	Canthaplatin and a PP2A inhibitor (LB) were encapsulated into PEG-b-PLGA micellar nanoparticles, which can overcome tumor resistance to cisplatin both in vitro and in vivo	Nanoparticles increased the uptake of canthaplatin by tumor cells. PP2A inhibitor suppressed DNA repair	^Citation87

Abbreviations: MGMT, O⁶-methylguanine methyltransferase; MMR, mismatch repair; LLL, trileucine; TfR, transferrin receptor; QDs, quantum dots; hENT1, human equilibrative nucleoside transporter 1; dCK, deoxycytidine kinase; CDA, cytidine deaminase; ABC, ATP-binding cassette; P-gp, P-glycoprotein; EMT, epithelial–mesenchymal transition; ER, estrogen receptor; BCRP, breast cancer resistance protein; PLGA, poly(lactic-co-glycolic acid); MnSOD, manganese superoxide dismutase; NPs, nanoparticles; PP2A, protein phosphatase 2A.

Table 2 Examples of overcoming tumor cell resistance to gemcitabine using nanomedicines

Nanocarriers	Main excipients/ingredients	Payload type	Outcome	Reference
Nanoparticles	PLGA	Gemcitabine	Nanoparticles showed higher cytotoxicity than free gemcitabine in gemcitabine resistant Panc-1 cells	^Citation194
	Chitosan	HER2 antibody, gemcitabine	Nanoparticles showed higher cytotoxicity than gemcitabine and targeting effect in MiaPaca-2 cells	^Citation208
	BSA	Gemcitabine	Nanoparticles showed higher cytotoxicity compared to free gemcitabine in Panc-1 cells. In addition, nanoparticles more effectively reduced the tumor volume in comparison with free gemcitabine	^Citation209
	Soy lecithin, GMS, Tween 20	4-(N)-GemC18	GemC18-SLNs showed more cytotoxic than free gemcitabine HCl in the hENT1-deficient CCRF CEM-AraC-8C cells and the dCK^−/− CCRF CEM-AraC-8D cells. GemC18-SLNs can also overcome gemcitabine resistance caused by RRM1 overexpression and RRM2 overexpression	^Citation68, ^Citation174, ^Citation182
	PLGA-b-PEG-OH	Gemcitabine, cisplatin	Nanoparticles increased cell sensitivity to gemcitabine compared to free gemcitabine in hCNT1-expressing cells	^Citation175
	Stearic acid	4-(N)-GemC18	Nanoparticles effectively reduced the viability of gemcitabine-resistant AsPC-1 cells in culture	^Citation195
	Squalene	Gemcitabine–squalene conjugate (SQ-dFdC)	SQdFdC self-assembled into nanoparticles, which were shown to overcome gemcitabine resistance in murine leukemia cells (ie, L1210 10K), human leukemia cells (ie, CCRF CEM-AraC-8C), and human pancreatic cancer cells (ie, Panc-1)	^Citation178, ^Citation180
	Lipid bilayer-MSNP (LB-MSNP)	Paclitaxel/gemcitabine	MSNP can suppress CDA expression, likely due to paclitaxel	^Citation183
Nanoassemblies (NAs)	Ethanol, aqueous dextrose solution	Squalenoyl conjugate of 5′-monophosphate-gemcitabine (SQdFdC-MP)	SQdFdC-MP NAs overcome gemcitabine resistance in Panc-1 and in L1210 10K cells caused by the downregulation of dCK	^Citation210
Liposomes	DPPC, Chol, DSPE-PEG2000	Gemcitabine	Liposomes were shown to inhibit the growth of a gemcitabine-resistant MDA-MB-231 breast cancer cell line	^Citation196
	DOPE, CHEMS, DSPE-mPEG2000	Gemcitabine	The pH-sensitive liposomes (PSL) were significantly more cytotoxic to gemcitabine resistant MIA PaCa-2 cells than gemcitabine	^Citation211
Micelles	PEG-PLA, stearic acid	4-(N)-GemC18	Polymeric micelles can effectively reduce the viability of gemcitabine-resistant AsPC-1 cells in culture	^Citation195
	PEG-PCC	Gemcitabine	Micelles significantly inhibited tumor growth in MiaPaCa-2 tumor cell-bearing mice	^Citation212
	Stearoyl-PEG	4-(N)-GemC18	Micelles can overcome gemcitabine resistance by inhibiting the expression of RRM1	^Citation193

Abbreviations: NPs, nanoparticles; SLNs, solid lipid nanoparticles; Gem, gemcitabine; BSA, bovine serum albumin; HER2, human epidermal growth factor receptor-2; PLGA, poly(lactic-co-glycolic) acid; PEG, polyethylene glycol; GMS, glyceryl monostearate; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phos-phocholinemonohydrate; Chol, cholesterol; DSPE, distearoyl phosphatidyl ethanolamine; DSPE-mPEG 2000, distearylphosphatidylethanolamine-N-(carbonyl methoxypolyethylene glycol-2000); PG, L-α-phosphatidyl-d,l-glycerol sodium salt; PEG-PCC, poly(ethyleneglycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate); PEG–PLA, poly(ethylene glycol)–poly(d,l-lactide); 4-(N)-GemC18, 4-(N)-stearoyl gemcitabine.

Figure 1 A schematic of the proposed mechanism by which 4-(N)-GemC18-SLNs overcome tumor cell resistance to gemcitabine.

Note: Reprinted from J Control Release. 169(1–2). Wonganan P, Lansakara PD, Zhu S, et al. Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle’s ability to overcome gemcitabine resistance caused by RRM1 overexpression.^17–27. Copyright 2013, with permission from Elsevier.¹⁷⁴

Abbreviations: CDA, (deoxy)cytidine deaminase; dCK, deoxycytidine kinase; dFdC, gemcitabine; dFdCMP, gemcitabine monophosphate; dFdCDP, gemcitabine diphosphate; dFdCTP, gemcitabine triphosphate; dNDP, deoxyribonucleoside diphosphate; dNTP, deoxyribonucleoside triphosphate; hENT, human equilibrative nucleoside transporter; NDP, ribonucleoside diphosphates; RR, ribonucleotide reductase.

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