Abstract 991: Secretory phospholipase A2 as a trigger for drug release in the treatment of triple-negative breast cancer

P21 activated kinases (or group I PAKs) are serine/threonine kinases whose expression is altered in prostate and breast cancers. PAK-1 activity is inhibited by the small molecule “Inhibitor targeting PAK-1 activation-3” (IPA-3), which has selectivity for PAK-1 but is metabolically unstable. Secretory Group IIA phospholipase A2 (sPLA2) expression correlates to increased metastasis and decreased survival in many cancers. We previously designed novel liposomal formulations targeting both PAK-1 and sPLA2, called Secretory Phospholipase Responsive liposomes or SPRL-IPA-3, and demonstrated their ability to alter prostate cancer growth. The efficacy of SPRL against other types of cancers is not well understood. We addressed this limitation by determining the ability of SPRL to induce cell death in a diverse panel of cells representing different stages of breast cancer, including the invasive but non-metastatic MCF-7 cells, and metastatic triple-negative breast cancer (TNBC) cells such as MDA-MB-231, MDA-MB-468, and MDA-MB-435. We investigated the role of sPLA2 in the disposition of these liposomes by comparing the efficacy of SPRL-IPA-3 to IPA-3 encapsulated in sterically stabilized liposomes (SSL-IPA-3), a formulation shown to be less sensitive to sPLA2. Both SSL-IPA-3 and SPRL-IPA-3 induced time- and dose-dependent decreases in MTT staining in all cell lines tested, but SPRL-IPA-3-induced effects in metastatic TNBC cell lines were superior over SSL-IPA-3. The reduction in MTT staining induced by SPRL-IPA-3 correlated to the expression of Group IIA sPLA2. sPLA2 expression also correlated to increased induction of apoptosis in TNBC cell lines by SPRL-IPA-3. These data suggest that SPRL-IPA-3 is selective for metastatic TNBC cells and that the efficacy of SPRL-IPA-3 is mediated, in part, by the expression of Group IIA sPLA2.

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A uPAR targeted nanoplatform with an NIR laser-responsive drug release property for tri-modal imaging and synergistic photothermal-chemotherapy of triple-negative breast cancer

Biomaterials Science ◽

10.1039/c9bm01495k ◽

2020 ◽

Vol 8 (2) ◽

pp. 720-738 ◽

Cited By ~ 1

Author(s):

Siming Yu ◽

Guanning Huang ◽

Riming Yuan ◽

Tianfeng Chen

Keyword(s):

Breast Cancer ◽

Drug Release ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Release Mechanism ◽

High Efficient ◽

Release Property ◽

Anticancer Mechanism ◽

Nir Laser

A multifunctional Ir complex(iii) loaded nanoplatform is designed for high efficient imaging and therapy of TNBC. The photothermal controlled Ir complex release mechanism and the synergistic anticancer mechanism are elucidated.

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Growth of Metastatic Triple-Negative Breast Cancer Is Inhibited by Deep Tumor-Penetrating and Slow Tumor-Clearing Chemotherapy: The Case of Tumor-Adhering Liposomes with Interstitial Drug Release

Molecular Pharmaceutics ◽

10.1021/acs.molpharmaceut.9b00812 ◽

2019 ◽

Vol 17 (1) ◽

pp. 118-131 ◽

Cited By ~ 1

Author(s):

Sally Stras ◽

Alaina Howe ◽

Aprameya Prasad ◽

Dominick Salerno ◽

Omkar Bhatavdekar ◽

...

Keyword(s):

Breast Cancer ◽

Drug Release ◽

Triple Negative Breast Cancer ◽

Triple Negative

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Theranostic Prodrug Vesicles for Reactive Oxygen Species-Triggered Ultrafast Drug Release and Local-Regional Therapy of Metastatic Triple-Negative Breast Cancer

Advanced Functional Materials ◽

10.1002/adfm.201703674 ◽

2017 ◽

Vol 27 (46) ◽

pp. 1703674 ◽

Cited By ~ 36

Author(s):

Fangyuan Zhou ◽

Bing Feng ◽

Tingting Wang ◽

Dangge Wang ◽

Zhirui Cui ◽

...

Keyword(s):

Breast Cancer ◽

Reactive Oxygen Species ◽

Drug Release ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Reactive Oxygen ◽

Oxygen Species ◽

Regional Therapy

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Drug Delivery: Activated Platelets‐Targeting Micelles with Controlled Drug Release for Effective Treatment of Primary and Metastatic Triple Negative Breast Cancer (Adv. Funct. Mater. 13/2019)

Advanced Functional Materials ◽

10.1002/adfm.201970086 ◽

2019 ◽

Vol 29 (13) ◽

pp. 1970086

Author(s):

Yujie Zhang ◽

Xi Zhu ◽

Xinli Chen ◽

Qinjun Chen ◽

Wenxi Zhou ◽

...

Keyword(s):

Breast Cancer ◽

Drug Delivery ◽

Drug Release ◽

Effective Treatment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Controlled Drug Release ◽

Activated Platelets

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Enhanced Paclitaxel Efficacy to Suppress Triple-Negative Breast Cancer Progression Using Metronomic Chemotherapy with a Controlled Release System of ElectrospunPoly-D-L-Lactide-Co-Glycolide (PLGA) Nanofibers

Cancers ◽

10.3390/cancers13133350 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3350

Author(s):

Ming-Yi Hsu ◽

Cheng-Hsien Hsieh ◽

Yu-Ting Huang ◽

Sung-Yu Chu ◽

Chien-Ming Chen ◽

...

Keyword(s):

Breast Cancer ◽

Body Weight ◽

Drug Release ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Specific Treatment ◽

Metronomic Chemotherapy ◽

Systemic Toxicity ◽

Conventional Chemotherapy ◽

Site Specific

Triple-negative breast cancer (TNBC) is highly aggressive and responds poorly to conventional chemotherapy. The challenge of TNBC therapy is to maximize the efficacies of conventional chemotherapeutic agents and reduce their toxicities. Metronomic chemotherapy using continuous low-dose chemotherapy has been proposed as a new treatment option, but this approach is limited by the selection of drugs. To improve antitumor therapeutic effects, we developed electrospun paclitaxel-loaded poly-D-L-lactide-co-glycolide (PLGA) nanofibers as a topical implantable delivery device for controlled drug release and site-specific treatment. The subcutaneously implanted paclitaxel-loaded nanofibrous membrane in mice was compatible with the concept of metronomic chemotherapy; it significantly enhanced antitumor activity, inhibited local tumor growth, constrained distant metastasis, and prolonged survival compared with intraperitoneal paclitaxel injection. Furthermore, under paclitaxel-loaded nanofiber treatment, systemic toxicity was low with a persistent increase in lean body weight in mice; in contrast, body weight decreased in other groups. The paclitaxel-loaded nanofibrous membranes provided sustained drug release and site-specific treatment by directly targeting and changing the tumor microenvironment, resulting in low systemic toxicity and a significant improvement in the therapeutic effect and safety compared with conventional chemotherapy. Thus, metronomic chemotherapy with paclitaxel-loaded nanofibrous membranes offers a promising strategy for the treatment of TNBC.

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PLGA-CS-PEG Microparticles for Controlled Drug Delivery in the Treatment of Triple Negative Breast Cancer Cells

Applied Sciences ◽

10.3390/app11157112 ◽

2021 ◽

Vol 11 (15) ◽

pp. 7112

Author(s):

Sandra Musu Jusu ◽

John David Obayemi ◽

Ali Azeko Salifu ◽

Chukwudalu Clare Nwazojie ◽

Vanessa Obiageli Uzonwanne ◽

...

Keyword(s):

Breast Cancer ◽

Polyethylene Glycol ◽

Drug Release ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

In Vitro Release ◽

Morphological Properties ◽

Cancer Drugs ◽

Kinetics Of

In this study, we explore the development of controlled PLGA-CS-PEG microspheres, which are used to encapsulate model anticancer drugs (prodigiosin (PGS) or paclitaxel (PTX)) for controlled breast cancer treatment. The PLGA microspheres are blended with hydrophilic polymers (chitosan and polyethylene glycol) in the presence of polyvinyl alcohol (PVA) that were synthesized via a water-oil-water (W/O/W) solvent evaporation technique. Chitosan (CS) and polyethylene glycol (PEG) were used as surface-modifying additives to improve the biocompatibility and reduce the adsorption of plasma proteins onto the microsphere surfaces. These PLGA-CS-PEG microspheres are loaded with varying concentrations (5 and 8 mg/mL) of PGS or PTX, respectively. Scanning electron microscopy (SEM) revealed the morphological properties while Fourier transform infrared spectroscopy (FTIR) was used to elucidate the functional groups of drug-loaded PLGA-CS-PEG microparticles. A thirty-day, in vitro, encapsulated drug (PGS or PTX) release was carried out at 37 °C, which corresponds to human body temperature, and at 41 °C and 44 °C, which correspond to hyperthermic temperatures. The thermodynamics and kinetics of in vitro drug release were also elucidated using a combination of mathematical models and the experimental results. The exponents of the Korsmeyer–Peppas model showed that the kinetics of drug release was well characterized by anomalous non-Fickian drug release. Endothermic and nonspontaneous processes are also associated with the thermodynamics of drug release. Finally, the controlled in vitro release of cancer drugs (PGS and PTX) is shown to decrease the viability of MDA-MB-231 cells. The implications of the results are discussed for the development of drug-encapsulated PLGA-CS-PEG microparticles for the controlled release of cancer drugs in treatment of triple negative breast cancer.

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