Gemcitabine Combination Nano Therapies for Pancreatic Cancer
Abstract
:1. Introduction
2. Gemcitabine—A Gold Standard Chemotherapeutic Agent for Pancreatic Cancer
2.1. Gemzar
2.2. HPMA Copolymer-Based Gemcitabine Formulation
2.3. Gemlip
2.4. Co-Delivery of Gemcitabine
3. Nano Formulations Involved in Gemcitabine Co-Administration and Co-Delivery
3.1. Liposomes
3.2. Nanogels
3.3. Micelles
3.4. Albumin Nanoparticles
3.5. Multifunctional Nanoparticles
3.6. Targeted Nanoparticles
4. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
PanCa | Pancreatic cancer |
PDAC | Pancreatic Ductal Adenocarcinoma |
GEM | Gemcitabine |
5-FU | 5-Fluorouracil |
PTX | Paclitaxel |
CIS | Cisplatin |
OXA | Oxaliplatin |
IRN | Irinotecan |
ERL | Erlotinib |
CAP | Capecitabine |
DOX | Doxorubicin |
LEU | Leucovorin |
MIT | Mitomycin |
CET | Cetuximab |
BEV | Bevacizumab |
ABL | Ablifercept |
SUN | Sunitinib |
TRA | Tramitinib |
PIM | Pimasertib |
dFdCDP | Difluorodeoxycytidine Diphosphate |
GEM-MOFs | Gemcitabine Loaded Metal Organic Frameworks |
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Nano-Systems | Drug Conjugate | Characterization | Utilization |
---|---|---|---|
(Micelles) GEM-PL | GEM-methoxy poly(ethylene glycol)-poly(lactic acid) (GEM-PL) | Particle size 112.2 ± 1.86 nm, zeta potential, 5.2 ± 1.26, encapsulation efficiency 92.5 ± 3.26 loading efficiency of 14.6 ± 1.29 and PDI(Poly dispersity index) 0.118. | In-vitro study was done using human colon cancer cell line HT29 and in-vivo studies for anticancer efficacy was done by injecting HT29 (5 × 106 cells) subcutaneously into right flank per mice and when tumor volume reached 100 mm3, 5 mg/kg fixed drug dose was administered 3 times for 12 days. In-vivo studies depicted improved blood circulation time with greater accumulation of the drug in tumor site with significant tumor regression. Formulation killed HT29 cells at a time dependent manner [39]. This study provides a valid reason required for further clinical research. |
(Micelles) C225—micelle-GEM-miR-205 | GEM-miR205-EGFR targeting Cetuximab antibody (C225) | Unmodified micelles containing GEM and miR-205 had the size of 76.6 ± 6 nm and zeta poteintial of 4.7 ± 1.65 mV. C225 conjugation was checked with standard BSA which was found to be 510 ug/mL C255 micelle 30% w/w for 10 gm polymer. | In-vitro studies were conducted using MIA PaCa-2 and in-vivo studies such as biodistribution and efficacy studies were done on NSC mice using an orthotopic tumor model where mice were implanted with GFP-transfected MIA PaCa-2 cells. In-vivo studies were conducted using a orthotopic pancreatic tumor model in 6 week old NSG mice injected with GFP transfected MIA PACA-2 cells [40]. |
(Micelles) PHC-GEMC18 | poly(ethylene glycol) (PEG) conjugated hydrophobic stearic acid derivative (C18) bonded through acid sensitive hydrazine bond-GEM | PHC size of 21.6 ± 0.6 nm zeta of 3.3 ± 1.1 mV PHC3%(GEM) size of 9.6 ± 3.7 nm zeta of 2.7 ± 1.2 mV PHC5%(GEM) size of 5.0 ± 0.1 nm zeta of −2.0 ± 0.7 mV. PHC10%(GEM) size of 9.7 ± 1.3 nm zeta of −2.2 ± 0.9 mV. | B16-F10 tumor was grown on C57BL/6 mice by subcutaneous inoculation in the right flank followed by treatment after day 6 of inoculation. As compared to GEM alone which is because of the increase in GEM18 accumulation [41]. |
(Micelle) GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC | G11 peptide of GEM conjugated with poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylenr carbonate-graft-Gemcitabine-graft-dodecanol micelle | Particle size of 26 ± 3 nm with a polydispersion index of 0.27 [42]. | MIA PaCa-2 cells have been used for the in-vivo studies and 6–8-week-old athymic nude mice were used for a orthotopic pancreatic cancer model for studying efficacy of the micelles after intraperitoneal injection of D-luciferin for bioluminescence studies. Increase in GEM delivery was seen up to 2.5 folds with an enhanced circulation half-life and EPR effect facilitating extravasation of micelle loaded drugs within the tumor microenvironment [43]. |
(Micelle) DTX-PEG-GEM | Docetaxel-Polyethylene-glycol-GEM | Particle size of 124.2 ± 5.7 nm and PDI of 0.132 ± 0.03 with critial micelle concentration range of 5–10 × 10−3 mg/mL. | In-vitro studies were done using MCF-7 and MDA-MB-231 for checking cellular internalization and uptake, In-vivo study used female Sprague dolly rats for carrying forward the pharmacokinetic and toxicity studies. Clathrin mediated endocytosis with 4.8 fold higher AUC value as compared to Gemzar alone was observed with a noteworthy decrease in tumor volume, increase in total survival, and reduction in hepatic, nephron, and hemolytic toxicity when administered with DTX-PEG-GEM nanoparticles [44]. |
(Micelle) P-GEM-DOX | Poly(HPMA-co-MA-GFLG-GEM co-MA-GFLG-DOX-co-MA-TyrNH2) | Molecular weight = 23.5 kDa, PD = 1.6, GEM = 6.4 wt %, Dox = 5.7 wt %, tyrNH2 = 1.0 mol %. | Dunning AT1rat prostate carcinoma cells were used for the in-vitro studies which involved drug release, cytotoxicity, and efficacy study of the formulation. In-vivo studies were conducted on male Copenhagen rats present with subcutaneous tumor. Enhanced circulation time with selectivity and localization at tumor-specific sites was seen with induction of apoptosis and inhibition of angiogenesis. In-vivo efficacy of P-GEM-DOX < free GEM, though co-conjugation enhanced in vitro efficacy [45]. |
(Micelle) GEM-LEMPs-DNA | PEGylated lipid bilayer cationic ε poly lysine co-polymer with GEM-(si-HIF1α) | Particle size of 60 nm with a hydrodynamic diameter according to DLS study, size was 141.8 nm zeta potential of GEM-LEMP-DNA was −34 mV, encapsulation efficiency of 42%. | Serum stability, cytotoxicity, PCR, and immunohistology studies were done using Panc-1 and B-16 melanoma cells. The in-vivo studies were conducted on female BALB/c mice to check the antitumor activity of the formulation. Formulation caused effecting silencing of HIF1α via siRNA and reduced drug-related resistance. The lipid layer protects si-HIF1 α from degradation thereby maintaining the integrity of the particle and preventing leakage of GEM [46]. |
(Micelle) GEM-C18-PLGA-MP | Stearoyl GEM incorporated within PLGA with surface functionalization with human serum albumin | GEMC18 content was found to be 488.9 ± 35.7 μg/mL with PLGA content of 1.71 ± 0.21 mg/mL corresponding to 285 ± 56 μg/mg or 28.6% ± 5.6% (w/w) of particle matrix, prodrug release of 13.2% ± 1.8% was seen after 5 days incubation. | SV-HUCC-1 normal urinary bladder cell was considered as control and urothelial cancer cell line 5637 and HT-1376 were used for a cell viability assay, studies for determining metabolic activity and for checking the cyto adhesive properties of formulation. GEMC18, when conjugated with PLGA microparticle, avoided intracellular drug activation thereby maintaining drug stability and covalent modification of the polymer with human serum albumin, led towards the enhanced binding capacity of the formulation with urothelial cells [47]. In-vivo studies using an animal model is still a requirement to confirm the pharmacokinetics of the formulation. |
(Micelle) FA-PEG-GEM-NPs | Folic acid conjugated GEM loaded surface modified chitosan nanoparticle | Particle size determined to be 184.3 ± 12.47 nm with a PDI of 0.22 ± 0.07 zeta potential of 21.1 ± 1.18 mV and encapsulation efficiency of 37.2% ± 2.2%. | In-vivo cytotoxic studies were done using lung epithelial cancer cell line A549 for a cytotoxic assay, drug release and cellular uptake. Balb/c mice were used to conduct the pharmacokinetic study. Significant cytotoxicity showed while GEM being delivered through nano formulation when treated to A549 cells showed more effective cellular internalization than free GEM [48]. |
(Metal-based) IONPs | GEM-siRNA-iron-oxide nanoparticles | Particle size of 80 nm. | Iron oxide was profoundly conjugated with CD44v6 targeted PanCa and GEM-siRNA conjugation with siBmi-1 oncogene to give multifunctional nanoparticle scFv-GEM-siBmi-1-NPs an in vivo anti-tumor synergistic activity [49]. |
(Metal-based) MIL-100 Nano-MOFs | Metal-organic framework of iron III trimesate nanoparticles-phosphate GEM | Encapsulation efficiency of phosphated GEM = 30.7% ± 0.8% which was almost 98%. | GEM-MP loaded NanoMOFs were studied on PANC-1 cells in a phosphate devoid medium with 50% of encapsulated drug released within 1 min after administration which stayed for 20 h [50]. |
(Metal-based) PS1-EPSMOs-GEM | Tetrasilylated porphyrin-ethylene periodic mesoporous organosilica nanoparticles | PS1-EPSMOs mean diameter (TEM) = 447 nm, zeta at pH 5.5 = −30 mV; zeta at pH 7.4 = −34 mV. | In-vivo delivery of drug was done on MCF-7 breast cancer cells. The porous structure provided high loading capacity and the addition of the porphyrin group provided photosensitivity to the nanoparticle [51]. In-vivo studies are yet to be done for confirming the significance of this formulation. |
(Metal-based) AuNC@BSA-MSN-GEM-DOX | Gold nanocluster bovine serum albumin clustered with mesoporous silica added with 32% GEM and DOX combined with albumin, attached electrostatically to formulation | Nanoparticle size = 150 nm, gold-protein conjugate zeta potential of −38 ± 1 mV for MSN-AuNC@BSA + DOX + GEM with AuNC content of 2.10 ± 0.23 and BSA 15.90 ± 1.80. | In-vitro study for the formulation was done using A549 lung cancer cells and biodistribution of formulation was seen in nude mice being previously injected subcutaneously with MIA-PaCa-2. Dual loading of GEM + DOX was 72 wt % which was four times higher than previous reports with less than 4% leakage of the loaded drug after a week in blood serum [52]. |
(Metal-based) PTX-GEM-LB-MSNNP | Lipid layer mesoporous-silica nanoparticle loaded with PTX and GEM | Hydrodynamic partilc size of 101 nm in saline and 112 nm with zeta potential of of −27.2 mV and −5.4 mV in saline plus 5% serum condition. | Cytotoxicity study, expression of cytidine deaminase and heme oxygenase via Western blot was done using PanC-1 cells and for the in-vitro studies, these cells were transfected with luciferase and implanted to grow subcutaneously within xenograft nude mice. Co-delivery of a dual drug caused enhanced phosphorylation with an increase in DNA-GEM interaction up to 13 fold and decreasing inactivated deaminated metabolite up to 4 folds producing synergistic codelivery of GEM and PTX [53]. |
(Metal base) GEM-Au DENPs/miR-21-inh | Ultrasound targeted microbubble-based dendrimer entrapped gold particle-Gemcitabne-miR-21 inhibitor | Mean particle size obtained was 154–276 nm with a surface charge range of 11–33 mV. | SW1990 cells were used to check the effect of the formulation on cytotoxicity, female athymic Balb/c mice were used to check the antitumor activity of the formulation. Uptake and apoptosis. The apoptosis percent of GEM–Au DENPs/miR-21i group (20.87% ± 0.81%) and GEM–Au DENPs/miR-21i + U group (25.43% ± 0.60%) which came up to be much more than the free GEM group (10.50% ± 0.56%) [40]. |
(Hydrogel) PNIPAM-b-PNAM-b-PNBOC | poly(N-isopropylacrylamide)-b-poly (4-acryloyl morpholine)-b-poly(2-(2-nitrobenzyl)oxy) carbonyl) amino)ethyl methacrylate)-GEM-Doxorubicin | Average hydrodynamic diameter was determined to be 68 nm. TEM observation gave spherical nanoparticles. | Extra micellar aqueous phase and the hydrophobic micellar core of formulation helped in the incorporation of a hydrophilic and hydrophobic drug [54]. This work showed the synthesis and characterization of formulation which needs follow up with in-vivo and in-vitro studies. |
Formulation | Target/Ligand | Process of Conjugation | Outcome |
---|---|---|---|
MPDNCs Poly(l-lysine) carboxylate PTX(PLL-PTX) + Hyaluronic acid conjugated GEM | CD44 | Electrostatic attraction between PLL-PTX and conjugation between HA-Gem through hydrolysable linkers. | Biliary cancer cells HuCCT1 and SCK have been used to check the targeting efficiency and therapeutic efficacy of the formulation. Xenograft Balb/c nude mice were used for checking in vivo drug efficacy. Cellular uptake of MPDNCs induced synergistic apoptosis [92]. |
GEM-AuNPs-C225 | EGFR | Incubation of AuNPs with 2 μg/mL C225 for 1 h at pH 7.8 proceeded by 1 h incubation with GEM 5 μg/mL. | Screening of PanCa cells such as PANC-1, AsPC-1, and MIA PACA-2 with EGFR expression enhanced the targeting efficiency of formulation with a significant reduction in cell proliferation and tumor growth in orthotopic nude mice injected with GFP transfected AsPC-1 cells [93]. |
EM-gold nanoparticle | Plectin-1 | Pyrimidine group within GEM provides free NH2 group where Gem has an ability to bind with the gold nanoparticle via electrostatic force of interaction. | Surface modulated GNPs with peptides used for plectin 1 targeting and conjugation with GEM showed higher cytotoxicity in AsPC-1 and PANC-1 cell lines with a significant in vivo antitumor efficacy of formulation when given via tail vein in female Balb/c mice with xenografted pancreatic tumor [94]. |
ATF-IONP-GEM (Amino terminal fragment-iron oxide nanoparticle-GEM) | Urokinase plasminogen activator receptor | Iron oxide nanoparticle are conjugated with amino terminal fragment peptide of uPA receptor domain through lysosomal cleavable tetra peptide linker. | In vitro studies to check drug cytotoxicity, drug targeting in PanCa cells was done using MIA PaCa-2. The anti-tumor activity was checked in-vivo with the help of MIA-PaCa-2 implanted xenograft model in nude mice. Drug dose given twice weekly. Endocytosis through receptor-mediated approach enabled the release of GEM within the cells which helped in intensifying MRI of the tumor and the presence of lysosomal cleavable bonds prevented the formulation from enzyme-based degradation [95]. |
GEM-Chitosan-Carbopol-MNPs | Folate receptor | Surface conjugation of Poly acrylic acid polymer with chitosan forming multilayer shell with a surface conjugation with folic acid. | PLC-PRF-5, DLD-1, and MDA-231 cell line respective to different cancers were used to carry on the in-vitro studies to depict cytotoxic activity of the formulation. Additional studies were also conducted to check for folate expression within cell. Targeting of folate receptor increased the chance of particles to surpass the cell membrane and make GEM available at tumor sites [96]. This study requires animal work for further validation of the formulation. |
Gem targeted TGFβi-MSNP | β-Kinase receptor | Co-precipitation method involved. PEI coating above the MSNP provide great number of non-complex hydrogens which gets attached to the nitrogen atom present in TGF B inhibitor LY364947 via hydrogen bonding. | Endothelial cells, human microvascular endothelial cells and human smooth muscle cells were used to mimic stromal environment and BxPC3 cancer cells were used for in-vitro studies and for implanting mice xenograft. Tumor bearing mice were injected IV. Formulation decreased vascular pericyte coverage by inhibiting TGF β pathway which is caused by LY364947 group of the formulation thereby enhancing efficient uptake of GEM-based IV liposomal formulation coming up as a two-way drug delivery approach [97]. |
GEM-C18-PEG-DSPE/TPGS | EGF-receptor | Stearic acid conjugated with GEM further been incorporated within PEG-DSPE/TPGS micelles where GEMC18 loaded micelles where prepared using solvent evaporation. | Human BxPC-3 were used to check the proliferation and cellular uptake of the formulation. Antitumor and pharmacokinetic studies were performed on mice injected with BxPC-3 intraperitoneally in the right flank. Formulation avoided GEM deamination which was noticed in free GEM leading towards enhanced GEM circulation time and 3-fold increased GEM concentration in tumor cells [96]. |
(GMP + VEGF)-LCP-AA | Sigma receptor | Phosphate group present in GEM interacts with calcium during the preparation of micro emulsion leading towards encapsulation of GEM and VEGF siRNA with a surface modification with PEG which increases particle retaining time within body. | 30–40% greater tumor inhibition with 8-fold reduced proliferation and decreased tumor microvessel density as compared to alone VEGF and GEM treatment was observed in H460 tumor induced mice with treatment given as IV injection, in vitro cytotoxic studies conducted using H460 non-small lung cancer cell. Multiple nucleic acid incorporation and targeting of sigma receptors found extensively on overexpressing cells [98]. |
Folic acid conjugated GEM loaded chitosan nanoparticle | Folate receptor | Normal conjugation and centrifugation process were utilized in synthesis of FA-conjugated and PEGylated GEM-NPs. | Significant cytotoxicity showed while GEM being delivered through nanoformulation when treated to A549 cells showed effective cellular internalization than free GEM. Balb/c mice were used to conduct the pharmacokinetic study with formulation injected through lateral tail vein [48]. |
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Samanta, K.; Setua, S.; Kumari, S.; Jaggi, M.; Yallapu, M.M.; Chauhan, S.C. Gemcitabine Combination Nano Therapies for Pancreatic Cancer. Pharmaceutics 2019, 11, 574. https://doi.org/10.3390/pharmaceutics11110574
Samanta K, Setua S, Kumari S, Jaggi M, Yallapu MM, Chauhan SC. Gemcitabine Combination Nano Therapies for Pancreatic Cancer. Pharmaceutics. 2019; 11(11):574. https://doi.org/10.3390/pharmaceutics11110574
Chicago/Turabian StyleSamanta, Kamalika, Saini Setua, Sonam Kumari, Meena Jaggi, Murali M. Yallapu, and Subhash C. Chauhan. 2019. "Gemcitabine Combination Nano Therapies for Pancreatic Cancer" Pharmaceutics 11, no. 11: 574. https://doi.org/10.3390/pharmaceutics11110574