Multifunctional PLGA Nanobubbles as Theranostic Agents: Combining Doxorubicin and P-gp siRNA Co-Delivery Into Human Breast Cancer Cells and Ultrasound Cellular Imaging

Abstract

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH-responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P-gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics.

PLGA‐PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction

“…Biodegradable, hydrophobic polymers are the most common materials for microsphere design, and they contain a single material,24, 25, 26 such as PLGA, ketal, polylactic acid (PLA), and chitosan microspheres, or a composite material,27, 28, 29 such as PLGA‐PEI microspheres, the characteristics of these microspheres are biocompatibility, security, nontoxicity, and rapid degradation. The other microspheres are mainly loaded with polypeptides and siRNA,30, 31, 32 such as liposome microspheres, and the main features of these microspheres are rapid degradation and absorption by cells through endocytosis, which can contribute to the release of polypeptides and siRNA. Additionally, a category of microspheres acts as the scaffolds of the cell, carrying the functional cell to the infarct site for the myocardial infarction treatment,33, 34 such as superparamagnetic microspheres, and the characteristics of these microspheres are porosity and high adsorption capacity, resulting in stable conjugation with the target cell.…”

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

“…76 Many studies exploited the feasibility of using nanomedicines to reverse DOX resistance. [76][77][78][79][80][81] For example, Wang et al showed that DOX encapsulated in mesoporous silica nanoparticles (MSNPs) can overcome MCF-7/MDR1 cell resistance to DOX. 79 Unsoy et al synthesized chitosan-coated magnetic nanoparticles for targeted delivery of DOX.…”

Paclitaxel-loaded and A10-3.2 aptamer-targeted poly(lactide-<em>co</em>-glycolic acid) nanobubbles for ultrasound imaging and therapy of prostate cancer

“…4 In recent years, polymer nanoparticles that can be used as drug delivery carriers or nonviral gene vectors have aroused high interest in nanomedicine. 5 Among these molecules, poly(lactideco-glycolic acid) (PLGA) is a biodegradable copolymer that has been approved by the United States Food and Drug Administration (FDA) for utilization as a scaffold in tissue engineering and in various drug or gene delivery systems. 6,7 Via the tricarboxylic acid cycle, the final products of the cellular metabolic conversion of PLGA are water and carbon dioxide, which are nontoxic molecules.…”

“…6,7 Via the tricarboxylic acid cycle, the final products of the cellular metabolic conversion of PLGA are water and carbon dioxide, which are nontoxic molecules. 5 Recently, biodegradable gas-filled nanobubbles (NBs) used as ultrasound (US) agents and fabricated from PLGA (denoted as PLGA NBs) have received widespread attention not only because these molecules can improve US signals but also because they can be used as drug carriers. 8 PLGA, as an NB shell with excellent biocompatibility, biodegradability, and mechanical strength, is preferred and popular for use in molecular imaging.…”