Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.
We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7618 Stevenson Center, Nashville, TN37235, United States.
Jacob N
JN
Lockhart
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7618 Stevenson Center, Nashville, TN37235, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN37212, United States.
David M
DM
Stevens
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7618 Stevenson Center, Nashville, TN37235, United States.
Dain B
DB
Beezer
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7618 Stevenson Center, Nashville, TN37235, United States.
Ariel
A
Kravitz
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7618 Stevenson Center, Nashville, TN37235, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN37212, United States. Electronic address: eva.harth@vanderbilt.edu.
Eva
E
Harth
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001682:Biological Availability; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004355:Drug Stability; D005260:Female; D005750:Gastric Juice / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000378:metabolism; D007419:Intestinal Secretions / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011794:Quercetin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D013629:Tamoxifen / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
D003432:Cross-Linking Reagents; D051544:Cytochrome P-450 CYP3A; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D014453:Glucuronosyltransferase; D011091:Polyesters; D011794:Quercetin; D013629:Tamoxifen; D000099148:UGT1A1 Enzyme
Chemotherapy; Combination therapy; Drug metabolism; Nanoparticle drug delivery; Quercetin; Tamoxifen