Lapatinib/Paclitaxel polyelectrolyte nanocapsules for overcoming multidrug resistance in ovarian cancer

Vergara, Daniele; Bellomo, Claudia; Zhang, Xingcai; Vergaro, Viviana; Tinelli, Andrea; Lorusso, Vito; Rinaldi, R.; Lvov, Yuri; Leporatti, Stefano; Maffia, Michele

doi:10.1016/j.nano.2011.10.014

Cited by 104 publications

(72 citation statements)

References 46 publications

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“…1H) (16); and multidrug resistant OVCAR-3 ovarian cancer cells, which are resistant to 5 μM ICI (Fig. 1I) and to paclitaxel, cisplatin, and other anticancer drugs (17,18). BHPI blocked proliferation in all 15 ERα + cell lines and at 10 μM had no effect on proliferation in all 12 ERα − cell lines tested (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 98%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

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Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα + cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP 3 ), which opens EnR IP 3 R calcium channels, rapidly depleting EnR Ca 2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca 2+ levels, but the open EnR IP 3 R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.estrogen receptor | drug discovery | breast cancer | unfolded protein response | ovarian cancer E strogens, acting via estrogen receptor α (ERα), stimulate tumor growth (1-3). Approximately 70% of breast cancers are ERα-positive and most deaths due to breast cancer are in patients with ERα + tumors (2, 4). Endocrine therapy using aromatase inhibitors to block estrogen production, or tamoxifen and other competitor antiestrogens, often results in selection and outgrowth of resistant tumors. Although 30-70% of epithelial ovarian tumors are ERα-positive (1), endocrine therapy is largely ineffective (5-7). After several cycles of chemotherapy, tumors recur as resistant ovarian cancer (5), and most patients die within 5 years (8).Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9-12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer requi...

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Section: Resultsmentioning

confidence: 98%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

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“…[14] The carriers can be further internalized by the tumor cells and release the drug intracellularly. [15] …”

Section: Introductionmentioning

confidence: 99%

Cubical Shape Enhances the Interaction of Layer‐by‐Layer Polymeric Particles with Breast Cancer Cells

Alexander

Kozlovskaya

Kuncewicz

et al. 2015

Adv Healthcare Materials

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Blood-borne objects display a non-spherical shape with in-flow dimensions much larger than the vascular endothelial fenestrations, yet, at the diseased state, are able to traverse through these fenestrations owing to their elasticity. The role of physical parameters including shape and elasticity in the behavior of objects found in the tumor microenvironment needs to be understood to ultimately enhance chemotherapy and minimize its side-effects. In this study, sphere and cube-shaped biocompatible elastic microparticles (EM) made via layer-by-layer (LbL) assembly of hydrogen-bonded tannic acid/poly(N-vinylpyrrolidone)/ (TA/PVPON) as hollow polymer shells and their rigid core-shell precursors (RM) are explored. In contrast to rigid 5-bilayer (TA/PVPON) core-shells, hollow shells are unrecognized by J774A.1 macrophages yet interact with endothelial and breast cancer cells. Internalization of cubical shells by HMVEC (endothelial) is 5-fold more efficient and 6- and 2.5-fold more efficient for MDA-MB-231 and by SUM159 (breast cancer cells), respectively, compared to spherical shells. The interaction of cubical (TA/PVPON)5 shells with endothelial cells is similar under 10 s−1 (characteristic of tumor vasculature) and 100 s−1 shear rate (normal vasculature) while it is decreased at 100 s−1 shear rate for the spherical shells. Our data suggest that cubical geometry promotes interaction of particles with breast cancer cells, while elasticity prevents engulfment by phagocytic cells in the tumor microenvironment.

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“…49,89 It is currently considered first-line treatment for ovarian cancer. PTX is a strongly hydrophobic compound, which poses significant formulation problems for intravenous administration.…”

Section: Paclitaxelmentioning

confidence: 99%

“…90 However, this compound causes significant undesirable adverse effects, making the development of delivery systems that do not require Kolliphor ® EL appealing. 89 Nanoparticles have been the most widely explored nanosystem for the delivery of PTX, with a variety of materials and functionalization techniques having been explored. 32 PTX nanoparticles have been widely successful in addressing the problems associated with PTX administration and efficacy; that is, the nanoparticles have successfully solubilized PTX and displayed adequate drug loading capacity; drug delivery is more targeted, even in nonfunctionalized nanoparticles, because of passive diffusion; and increased therapeutic efficacy in vivo, as a result of targeted delivery, increased cellular uptake, protection of PTX from enzymatic degradation and inactivation, and an increase in circulation half-life.…”

Section: Paclitaxelmentioning

confidence: 99%

Overview of the role of nanotechnological innovations in the detection and treatment of solid tumors

Frank¹,

Tyagi²,

Tomar³

et al. 2014

IJN

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Nanotechnology, although still in its infantile stages, has the potential to revolutionize the diagnosis, treatment, and monitoring of disease progression and success of therapy for numerous diseases and conditions, not least of which is cancer. As it is a leading cause of mortality worldwide, early cancer detection, as well as safe and efficacious therapeutic intervention, will be indispensable in improving the prognosis related to cancers and overall survival rate, as well as health-related quality of life of patients diagnosed with cancer. The development of a relatively new field of nanomedicine, which combines various domains and technologies including nanotechnology, medicine, biology, pharmacology, mathematics, physics, and chemistry, has yielded different approaches to addressing these challenges. Of particular relevance in cancer, nanosystems have shown appreciable success in the realm of diagnosis and treatment. Characteristics attributable to these systems on account of the nanoscale size range allow for individualization of therapy, passive targeting, the attachment of targeting moieties for more specific targeting, minimally invasive procedures, and real-time imaging and monitoring of in vivo processes. Furthermore, incorporation into nanosystems may have the potential to reintroduce into clinical practice drugs that are no longer used because of various shortfalls, as well as aid in the registration of new, potent drugs with suboptimal pharmacokinetic profiles. Research into the development of nanosystems for cancer diagnosis and therapy is thus a rapidly emerging and viable field of study.

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Lapatinib/Paclitaxel polyelectrolyte nanocapsules for overcoming multidrug resistance in ovarian cancer

Cited by 104 publications

References 46 publications

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Cubical Shape Enhances the Interaction of Layer‐by‐Layer Polymeric Particles with Breast Cancer Cells

Overview of the role of nanotechnological innovations in the detection and treatment of solid tumors

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