betadex and Triple-Negative-Breast-Neoplasms

Topics: Animals; Antineoplastic Agents; Benzimidazoles; beta-Cyclodextrins; Cell Line, Tumor; Cell Movement; Cell Survival; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Female; Ferrous Compounds; Heparin, Low-Molecular-Weight; Hydrogen-Ion Concentration; Metallocenes; Mice, Inbred BALB C; Nanoparticles; Neoplasm Invasiveness; Pentacyclic Triterpenes; Polyethyleneimine; Polylactic Acid-Polyglycolic Acid Copolymer; Reactive Oxygen Species; Stimuli Responsive Polymers; Triple Negative Breast Neoplasms; Tumor Burden

Chemotherapy is the primary therapy for triple-negative breast cancer (TNBC) and the tumor-targeted delivery of chemotherapeutic drugs is necessary to minimize their side effects on normal tissues. TNBC cells display addictions to glutamine in culture, and the levels of the glutamine transporter, alanine-serine-cysteine transporter 2 (ASCT2), are elevated in many types of cancer. However, glutamine- or ASCT2-based carriers have not been used in tumor-targeted drug delivery. In this study, a novel derivative of β-cyclodextrin (β-CD), glutamine-β-cyclodextrin (GLN-CD), was developed by conjugating glutamine with the 6-hydroxy of β-CD, and GLN-CD was then used to prepare doxorubicin (DOX) inclusion complexes (DOX@GLN-CD) for TNBC treatment. GLN-CD and glutamine have similar ASCT2-binding sites, and GLN-CD has the potential to enter cells through ASCT2-dependent facilitated diffusion. An increase in the degree of substitution did not promote binding between GLN-CD and ASCT2. GLN-CD and DOX formed inclusion complexes at a molar ratio of 1 : 1. DOX@GLN-CD specifically accumulated in TNBC cells, including MDA-MB-231 and BT549 cells, where it subsequently induced G2/M blockade and apoptosis, but hardly affected nontumorigenic MCF10A cells. l-γ-Glutamyl-p-nitroanilide (GPNA), which is a specific inhibitor of ASCT2, antagonistically decreased the cellular uptake of DOX@GLN-CD by TNBC cells, which further confirmed the role of ASCT2 in DOX@GLN-CD transport. In vivo, DOX@GLN-CD accumulated specifically in tumors, achieved improved outcomes and minimized the toxic effects on main organs at the same dose as DOX. As a novel derivative of β-CD, GLN-CD is an effective carrier that can specifically deliver DOX to TNBC cells via targeting ASCT2 and minimize its uptake by normal cells.

Topics: Amino Acid Transport System ASC; Animals; Apoptosis; beta-Cyclodextrins; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Glutamine; Humans; Mice, Inbred BALB C; Mice, Nude; Minor Histocompatibility Antigens; Triple Negative Breast Neoplasms

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-β-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.

Topics: Albendazole; Animals; Antiparasitic Agents; beta-Cyclodextrins; Biological Availability; Cell Proliferation; Cyclodextrins; Drug Repositioning; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Random Allocation; Treatment Outcome; Triple Negative Breast Neoplasms; X-Ray Diffraction

Breast cancer remains the second leading cause of cancer deaths for women in the U.S. The need for new and alternative strategies to treat this cancer is imperative. Here we show the optimization of our nanochannel delivery system (nDS) for constant and sustained delivery of docetaxel (DTX) for thetreatment of triple negative breast cancer. DTX is a highly hydrophobic drug, making it difficult to reach the therapeutic levels when released in aqueous solutions from our implantable delivery system. To overcome this challenge and test the release of DTX from nDS, we prepared DTX/2-hydroxypropyl β-cyclodextrin (DTX/HPCD) inclusion complexes in different molar ratios. The 1:10 DTX/HPCD complex achieved 5 times higher solubility than the 1:2 complex and 3 times higher in vitrorelease of DTX than with free DTX. When released in SCID/Beige mice from nanochannel system, the DTX/HPCD complex showed reduced tumor growth, comparable to the standard bolus injections of DTX, indicating that the structural stability and biological activity of DTX were retained in the complex, after its diffusion through the nanochannel system.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; beta-Cyclodextrins; Delayed-Action Preparations; Docetaxel; Drug Delivery Systems; Female; Humans; Mice; Mice, SCID; Taxoids; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

With the aim to find novel therapeutical approaches for triple-negative breast cancer (TNBC) treatment, we have developed a powder for i.v. injection based on cyclodextrins and docetaxel (DTX)-loaded polyethyleneglycol-poly(epsilon-caprolactone) nanoparticles (DTX-NPs). Nanoparticles are designed to concentrate at tumor level by enhanced permeability and retention effect and release drug cargo at a sustained rate in the blood and in tumor interstitium. DTX-NPs of around 70 nm, shielding proteins and allowing a sustained DTX release for about 30 days, were produced by melting sonication technique. DTX-NPs were associated to hydroxypropyl-β-cyclodextrin to give a powder for injection with excellent dispersibility and suitable for i.v. administration. DTX-NPs were as efficient as free DTX in inhibiting cell growth of MDA-MB231 cells, even at low concentrations, and displayed a comparable in vivo antitumor efficacy and better survival in a TNBC animal model as compared with DTX commercial formulation (Taxotere(®)). In conclusion, PEGylated biodegradable DTX-NPs highlighted their potential in the treatment of aggressive TNBC providing a foundation for future clinical studies.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; beta-Cyclodextrins; Blood Proteins; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Docetaxel; Ethylene Glycols; Female; Humans; Mammary Neoplasms, Experimental; Mice, Nude; Nanoparticles; Polyesters; Powders; Taxoids; Triple Negative Breast Neoplasms; Tumor Burden