gambogic-acid and Triple-Negative-Breast-Neoplasms

Amino acid-based poly(ester urea urethane) (AA-PEUU) is developed from amino acid-based ester urea building blocks interconnected with urethane blocks functionalized with poly(ethylene glycol) (PEG). Each functional block consists of structural design features that could impact the properties and performances of AA-PEUU as a nanocarrier for the systemic delivery of gambogic acid (GA). The multifunctional AA-PEUU structure provides broad tunability to enable the optimization of nanocarriers. The study investigates the structure-property relationship by fine-tuning the structure of AA-PEUU, including the amino acid type, hydrocarbons, the ratio of functional building blocks, and PEGylation, to identify the nanoparticle candidate with optimized delivery performances. Compared to free GA, the optimized PEUU nanocarrier improves the intratumoral distribution of GA by more than 9-fold, which significantly enhances the bioavailability and persistence of GA after intravenous administration. In an MDA-MB-231 xenograft mouse model, GA delivered by the optimized AA-PEUU nanocarrier exhibits significant tumor inhibition, apoptosis induction, and the anti-angiogenesis effect. The study demonstrates the potency of engineering AA-PEUU nanocarriers with tailor-designed structures and versatile tunability for the systemic delivery of therapeutics in the treatment of triple negative breast tumor.

Topics: Amino Acids; Animals; Esters; Humans; Mice; Nanoparticles; Triple Negative Breast Neoplasms; Urea; Urethane

Therapy for triple-negative breast cancer (TNBC) is a global problem due to lack of specific targets for treatment selection. Cancer stem cells (CSCs) are responsible for tumor formation and recurrence but also offer a promising target for TNBC-targeted therapy. Here, zirconium-89 (. The biological basis of CS targeting CD44 for cancer therapy was investigated by detecting the expression of CD44 in TNBC CSCs and TNBC tissues. Molecular docking and dynamics simulations were performed to investigate the molecular basis of CS targeting CD44 for cancer therapy. Gambogic acid (GA)-loaded,. CD44 is overexpressed in TNBC CSCs and tissues. Molecular docking and dynamics simulations showed that CS could be stably docked into the active site of CD44 in a reasonable conformation. Furthermore,. The GA-loaded,

Topics: Adult; Aged; Animals; Antineoplastic Agents; Cell Line, Tumor; Chitosan; Female; Humans; Hyaluronan Receptors; Liposomes; Mice, Nude; Middle Aged; Molecular Docking Simulation; Molecular Targeted Therapy; Neoplastic Stem Cells; Positron-Emission Tomography; Radioisotopes; Tissue Distribution; Triple Negative Breast Neoplasms; Xanthones; Xenograft Model Antitumor Assays; Zirconium

Paclitaxel is the most frequently used therapy regimen for triple‑negative breast cancer (TNBC). However, chemoresistance frequently occurs, leading to enhanced failure rates of chemotherapy in TNBC; therefore, novel biological therapies are urgently needed. Gambogic acid (GA) has potent anticancer effects and inhibits tumor growth in several types of human cancer. However, the effects of GA on paclitaxel‑resistant TNBC remain unknown. In the present study, the Cell Counting Kit‑8 assay was used to examine the effect of GA and/or paclitaxel on the viability of TNBC cells; flow cytometry was used to examine the effects of GA on cell apoptosis; and western blotting and reverse transcription‑quantitative PCR were used to determine the effects of GA on the expression of sonic hedgehog (SHH) signaling pathway target genes. The present results indicated that GA significantly inhibited the viability and enhanced the rate of apoptosis in paclitaxel‑resistant MDA‑MB‑231 cells via activating the SHH signaling pathway. In vivo experiments confirmed that GA treatment enhanced the sensitivity of MDA‑MB‑231 cells to paclitaxel via the SHH signaling pathway. In conclusion, the combination of GA with paclitaxel may increase the antitumor effects on paclitaxel‑resistant TNBC via downregulating the SHH signaling pathway.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Hedgehog Proteins; Humans; Paclitaxel; Signal Transduction; Triple Negative Breast Neoplasms; Xanthones

Gambogic acid (GA) is a natural anti-tumor drug whose application is restricted by its poor aqueous solubility and inefficient bioavailability. Developing nanomaterials with excellent biocompatibility can amplify the therapeutic effects of GA. In this study, a tumor-targeted redox controllable self-assembled nano-system with magnetic enhanced EPR effects (mPEG-HA/CSO-SS-Hex/SPION/GA) was developed to improve the anticancer efficacy of GA. The nano-system is constituted by three layers: the outer layer is mono-aminated poly(ethylene glycol) grafted hyaluronic acid (mPEG-HA), which can target the CD44 receptor in breast cancer cells; the middle layer consists of disulfide linked hexadecanol (Hex) and chitosan oligosaccharide (CSO) to control the drug release by reduction response; the core layer is superparamagnetic iron oxide nanoparticles (SPION), which can enhance the EPR effect by magnetic guidance and contribute to GA entrapment. Different experiments were performed to characterize the complex self-assembly, and the cytotoxicity, pharmacokinetics, and in vivo antitumor activity of the self-assembly were investigated to evaluate its anti-tumor effects. The results revealed that mPEG-HA/CSO-SS-Hex/SPION/GA is an excellent nanosystem with appropriate size and sensitive responsiveness; it can accumulate in tumor sites and achieve excellent therapeutic effects on triple-negative breast cancer (TNBC). In summary, a CD44-targeted redox-triggered self-assembly nanosystem with magnetic enhanced EPR effects was developed for effective amplification of GA; it has potential to act as an effective carrier in drug delivery for chemotherapy of TNBC.

Topics: Animals; Biological Availability; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Carriers; Female; Humans; Hyaluronan Receptors; Hyaluronic Acid; Magnetite Nanoparticles; MCF-7 Cells; Mice; Oxidation-Reduction; Polyethylene Glycols; RAW 264.7 Cells; Tissue Distribution; Triple Negative Breast Neoplasms; Xanthones; Xenograft Model Antitumor Assays

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based combination therapy and gene therapy are new strategies to potentially overcome the limitations of TRAIL, however, the lack of efficient and low toxic vectors remains the major obstacle. In this study, we developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(d,l-lactide-co-glycolide) (PEI-PLGA) nanoparticle (NP) system for targeted co-delivery of TRAIL plasmid (pTRAIL) and gambogic acid (GA) in triple-negative breast cancer (TNBC) therapy. GA was encapsulated into the core of the PEI-PLGA NPs while pTRAIL was adsorbed onto the positive NP surface via charge adsorption. The coating of HA on PEI-PLGA NPs functions as a targeting ligand by binding to CD44 receptor of TNBC cells and a shell to neutralize the excess positive charge of inner NPs. The resultant pTRAIL and GA co-loaded HA-coated PEI-PLGA NPs exhibited spherical shape (121.5 nm) and could promote the internalization of loaded cargoes into TNBC cells through the CD44-dependent endocytic pathway. The dual drug-loaded NPs significantly augmented apoptotic cell death in vitro and inhibited TNBC tumor growth in vivo. This multifunctional NP system efficiently co-delivered GA and pTRAIL, thus representing a promising strategy to treat TNBC and bringing forth a platform strategy for co-delivery of therapeutic DNA and chemotherapeutic agents in combinatorial TNBC therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Humans; Hyaluronan Receptors; Hyaluronic Acid; Lactic Acid; MCF-7 Cells; Mice; Nanoparticles; Plasmids; Polyethyleneimine; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; TNF-Related Apoptosis-Inducing Ligand; Triple Negative Breast Neoplasms; Xanthones

Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor aqueous solubility. In the present study, positively charged PEGylated liposomal formulation of GA (GAL) was developed for parenteral delivery for the treatment of triple-negative breast cancer (TNBC). The GAL was formulated with a particle size of 107.3 ± 10.6 nm with +32 mV zeta potential. GAL showed very minimal release of GA over 24 h period confirming the non-leakiness and stability of liposomes. In vitro cytotoxicity assays showed similar cell killing with GA and GAL against MDA-MB-231 cells but significantly higher inhibition of HUVEC growth was observed with GAL. Furthermore, GAL significantly (p < 0.05) inhibited the MDA-MB-231 orthotopic xenograft tumor growth with >50% reduction of tumor volume and reduction in tumor weight by 1.7-fold and 2.2-fold when compared to GA and controls, respectively. Results of western blot analysis indicated that GAL significantly suppressed the expression of apoptotic markers, bcl2, cyclinD1, survivin and microvessel density marker-CD31 and increased the expression of p53 and Bax compared to GA and control. Collectively, these data provide further support for the potential applications of cationic GAL in its intravenous delivery and its significant role in inhibiting angiogenesis against TNBC.

Topics: Antineoplastic Agents; Breast Neoplasms; Cations; Cell Line, Tumor; Drug Delivery Systems; Female; Humans; Liposomes; Particle Size; Polyethylene Glycols; Triple Negative Breast Neoplasms; Xanthones; Xenograft Model Antitumor Assays