DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy

Abstract

PEGylated liposomes have transformed chemotherapeutic use of doxorubicin by reducing its cardiotoxicity; however, it remains unclear whether liposomal doxorubicin is therapeutically superior to free doxorubicin. Here, we demonstrate a novel PEGylated liposome system, named DAFODIL (Doxorubicin And 5-Flurouracil Optimally Delivered In a Liposome) that inarguably offers superior therapeutic efficacies compared to free drug administrations. Delivery of synergistic ratios of this drug pair led to greater than 90% reduction in tumor growth of murine 4T1 mammary carcinoma in vivo. By exploiting synergistic ratios, the effect was achieved at remarkably low doses, far below the maximum tolerable drug doses. Our approach re-invents the use of liposomes for multi-drug delivery by providing a chemotherapy vehicle which can both reduce toxicity and improve therapeutic efficacy. This methodology is made feasible by the extension of the ammonium-sulfate gradient encapsulation method to nucleobase analogues, a liposomal entrapment method once conceived useful only for anthracyclines. Therefore, our strategy can be utilized to efficiently evaluate various chemotherapy combinations in an effort to translate more effective combinations into the clinic.

Recent advances in the preparation and application of multifunctional iron oxide and liposome-based nanosystems for multimodal diagnosis and therapy

“…This nanosystem offered superior therapeutic efficacies compared with free drug administrations and less cytotoxicity. The synergistic effect led to a high reduction (90%) in the tumour growth of murine 4T1 mammary carcinoma in vivo [135]. Example of immunotherapy combined with PDT was reported by Mir et al [136].…”

Dual Functionality nanobioconjugates: a New Tool for Intracellular Bacterial Targeting in Cancer cells?

“…Perhaps it is time to cast a fresh look at the present drug delivery approaches and re-engineer them to allow facile dual-targeting of both cell types simultaneously. A recent study by Mitragotri's group at University of California, Berkeley (CA, USA) showed an enhanced synergistic combinatorial therapy for tumor targeting by co-packaging two anticancer drugs in the same liposome carrier [15]. Such incorporation and synergistic use of more than one drug to enhance the efficacy of standard therapies is indeed the latest trend in targeted deliveries.…”

A combined approach for predicting the cytotoxic effect of drug-nanoaggregates

“…[7][8][9][10][11] As compared to the pure drug, PDCs show improved solubility and therapeutic efficacy, as well as reduced side effects and multi-drug resistance. [12][13][14] While conjugation to a polymer carrier was expected to prevent drug aggregation owing to slow and controlled drug release from the polymer backbone, it has been found that the polymer carrier does promote assembly of drugs, prior to or upon release, and play a role in tuning the architecture of drug nanoaggregates. We have experienced this effect while working on dextran-etoposide conjugates.…”