Biodegradable Nanovectors As a Direct Platform for the Controlled Delivery of Chemotherapeutic Drugs Against Childhood ALL
| Autor: | David C Williams, Benjamin C Ede, Allison Blair, Paraskevi Diamanti |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Drug
business.industry medicine.medical_treatment media_common.quotation_subject Immunology Intraperitoneal injection Cell Biology Hematology Pharmacology medicine.disease Biochemistry Leukemia Pharmacokinetics Drug delivery Toxicity medicine Distribution (pharmacology) business Dexamethasone medicine.drug media_common |
| Zdroj: | Blood. 136:9-9 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Drugs used to treat childhood acute lymphoblastic leukemia (ALL), both clinically and experimentally, are often highly insoluble making drug delivery inefficient due to precipitation and poor distribution. Toxicity is also a major issue owing to the high levels of harmful solvents used to solubilize drugs for administration. Therefore, identifying strategies to enhance the stability and solubility of poorly soluble drugs is an ongoing challenge. Data from clinical trials indicates that the pharmacokinetics of dexamethasone (Dex), commonly used in induction regimens for ALL, vary considerably between patients (pts) and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Copolymeric nanovectors (NV) are an excellent candidate for the delivery of insoluble drugs. However, despite reports of multiple systems, the fabrication processes often rely on complex methodologies with purification steps to remove harmful chemicals used to load drugs. To bypass these fabrication issues, we have shown that fully biodegradable copolymer NV comprised of poly(ethylene glycol)-block-poly (trimethylene carbonate) (PEG-PTMC) can sequester highly insoluble drugs (with almost total efficiency) through a direct hydration process in 5 minutes, eliminating the need for purification and use of harmful solvents. The aim of this study was to assess the effects of this systemin vitroandin vivousing Dex. NV were formulated with Dex or 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, a near infrared insoluble dye) to model NV distributionin vivo. Both Dex and DiR solubilization was initiated using residual (0.1% ALL cells) animals were treated daily for 5 days, over 4 weeks with 2.5 mg/kg Dex via intraperitoneal injection (IP). Both Dex-NV and free Dex delayed disease progression until day 18 in pt 1, and until after treatment cessation in pts 2 and 3 with disease levels of 0.24±0.1% and 0.55±0.1% near the end of treatment, respectively. In contrast, leukemia engraftment increased immediately following engraftment in placebo controls. Dex-NV and free Dex significantly improved the survival of NSG by up to 27 days (P Disclosures No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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