Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

Abstract

Purpose Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding. Methods Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib. Results High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (−15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC 50 reduction on the non-targeted imatinib liposomes from 910 to 150 μM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice. Conclusion These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting.

Colon cancer: Cancer stem cells markers, drug resistance and treatment

“…The drugs used in combination should act by different 384 mechanisms, have some efficacy by themselves, have different 385 toxicity profiles and different mechanisms of resistance develop-386 ment. Another very promising strategy is the development of the 387 drug delivery system based on liposomes to enhance drug delivery 388 to tumour cells and to reduce plasma protein binding [80]. Novel 389 systematic computational tool DrugComboRanker to prioritize 390 synergistic drug combinations and uncover their mechanisms of 391 action in cancer treatment was described [81].…”

Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes

“…HSPC is a neutral lipid which has been used a lot in liposome preparation. [33][34][35] CHOL was a common component in miRNA carriers, and introducing CHOL as a component of certain DNA/RNA carriers was reported to be a factor in improving gene transfection in vivo. 36 In our study, CHOL played a dual role in the delivery of miRNA.…”

“…Meanwhile, both RL and Tf-RL possessed slight negative zeta potentials, which might be due to the presence of the negatively charged lipid mPEG 2000 -DSPE in the formulation, and this also helps the liposomes get a good physical stability against aggregation and fusion. 35 The efficacy of liposome was further examined in vitro in HepG2 and Hep3B cell lines, which are the Tf receptor over-expressed HCC cell lines. As expected, our Tf-CL was more efficiently taken up by the HepG2 cells, which was confirmed by the CL uptake study.…”

Nanotechnology-based drug delivery systems for the treatment of Alzheimer&rsquo;s disease

“…240,241 Various processes can be used to prepare liposomes, such as hydration of a thin lipid film [242][243][244] followed by agitation, [245][246][247][248] sonication, [249][250][251][252][253][254] extrusion, 251,[255][256][257][258] high-pressure homogenization, [259][260][261][262] or reverse-phase evaporation. [263][264][265][266] Liposomes may contain a single lipid bilayer or multiple bilayers around the inner aqueous compartment and are therefore classified as unilamellar and multilamellar, respectively.…”