A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy

Cristina Ioana Barbălată,Valentin-Florian Rauca,Alina Silvia Porfire,Ioan Tomuță,Alina Sesarman,Manuela Banciu,Dana Muntean,Cristian Moldovan,Rareș Știufiuc,Alin Moldovan

doi:10.3390/pharmaceutics13101526

Cristina Ioana Barbălată, Valentin-Florian Rauca + Show 8 more

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https://doi.org/10.3390/pharmaceutics13101526

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Abstract

An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.

Highlights

IntroductionA 2020 statistic from the World Health Organization highlighted that colorectal cancer (CRC) is the third most common type of cancer, and the second one based on the number of deaths [1]
The implementation of the Quality by Design (QbD) concept in the development of SIM-DOX-LCL was conducted in accordance with international guidelines, namely International Conference on Harmonization (ICH) guideline for pharmaceutical development Q8(R2) and the guidance for industry for liposome drug products approved by the Food and Drug Administration (FDA) [37,39]
The experience gained from the development of Doxil® evidenced that the therapeutic activity of liposomes in cancer treatment is dependent on the quality profile of the formulation [13]; the quality target product profile (QTPP) of SIM-DOX-LCL included a range of features which should ensure the antiproliferative effect of the formulation in cancer treatment

Summary

Introduction

A 2020 statistic from the World Health Organization highlighted that colorectal cancer (CRC) is the third most common type of cancer, and the second one based on the number of deaths [1]. The conventional therapy for CRC consists of surgical resection of the tumor, chemotherapy, radiotherapy, or a combination of these [2]. Chemotherapy implies the use of high concentrations of chemotherapeutic drugs with low therapeutic indexes and reduced specificity, which further leads to the appearance of an increased number of adverse reactions with low patient compliance and complementary healthcare support/costs [3]. More and more cancerous cells develop drug resistance to chemotherapy through different mechanisms of action, emphasising the need to explore

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