Electroneutral polymersomes for combined cancer chemotherapy

Abstract

Combination cancer chemotherapy provides an important treatment tool, both as an adjuvant and neoadjuvant treatment, this shift in focus from mono to combination therapies has led to increased interest in drug delivery systems (DDS). DDSs, such as polymersomes, are capable of encapsulating large amounts of multiple drugs with both hydrophilic and hydrophobic properties simultaneously, as well as offering a mechanism to combat multi drug resistant cancers and poor patient tolerance of the cytotoxic compounds utilised. In this article, we report the formulation and evaluation of a novel electroneutral polymersome capable of high encapsulation efficacies for multiple drugs (Doxorubicin, 5-Fluorouracil and leucovorin). The in-vivo biodistribution of the polymersome were established and they were found to accumulate largely in tumour tissue. Polymersome encapsulating the three chemotherapeutic drugs were assessed both in-vitro (BxPC-3 cell line) and in-vivo (following intratumoral and intravenous administration) and compared with the same concentration of the three drugs in solution. We report better efficacy and higher maximum tolerated dose for our combination drug loaded polymersomes in all experiments. Furthermore, intratumorally injected combination drug loaded polymersomes exhibited a 62% reduction in tumour volume after 13 days when compared with the free combination solutions. A smaller differential of 13% was observed for when treatment was administered intravenously however, importantly less cardiotoxicity was displayed from the polymersomal DDS. In this study, expression of a number of survival-relevant genes in tumours treated with the free chemotherapy combination was compared with expression of those genes in tumours treated with the polymersomes harbouring those drugs and the significance of findings is discussed. STATEMENT OF SIGNIFICANCE: The shift in focus from mono to combination chemotherapies has led to an increased interest in the role of drug delivery systems (DDS). Liposomes, although commercialized for mono therapy, have lower loading capacities and stability than their polymeric counterpart, polymersomes. Polymersomes are growing in prevalence as their advantageous properties are better understood and exploited. Here we present a novel polymersome for the encapsulation of three anticancer compounds. This is the first time this particular polymersome has been used to encapsulate these three compounds with both an in-vitro and in-vivo evaluation carried out. This work will be of interest to those in the field of combination therapy, drug delivery, drug toxicity, multidrug resistance, liposomes, DDS and polymersomes.

Polymers and Polymer Nanocomposites for Cancer Therapy

“…The encapsulation of the three drugs was assessed both in vitro and in vivo and compared to the same concentration of the three drugs in solution. A higher efficacy and higher maximum tolerance dose for the combination drug-loaded polymersomes was reported [124].…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…However, pitfalls and caveats for different types of nanocarriers still exist. For example, liposomes are known to encapsulate hydrophobic and hydrophilic drugs [187] and are extensively applied in drug delivery because of their advantages with prolonged efficacy, reduced toxicity, and tumortargeting properties after modification. However, many liposomal preparations were unexpectedly withdrawn in clinical trials, even though they are very successful in previous animal models [188].…”

“…In addition, the subcutaneous tumor model grows rapidly, and its blood vessels are leaky, leading to an overestimation of the EPR effect [189]. Furthermore, the limitations of liposomes include rapid metabolism and degradation, as well as instability and difficulty in storage [187]. On the other hand, polymer nanoparticles have poor stability in physiological environments and may exchange with other physiological components, restricting their applications.…”

Nanoparticulate RNA delivery systems in cancer

“…Polymersomes are the spherical hollow bodies, tailored to respond to the desired stimulus and used to deliver both hydrophilic and hydrophobic drugs. 37,38 For instance, diblock copolymer of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly ( 38,41 In this method, the polymer solution was mixed with chloroform/methanol solution and left in a vacuum to produce a thin film of polymer. This thin film was subsequently rehydrated with aqueous NaOH to generate the polymersomes.…”

“…Polymersomes are the spherical hollow bodies, tailored to respond to the desired stimulus and used to deliver both hydrophilic and hydrophobic drugs 37,38 . For instance, diblock copolymer of poly(ethylene glycol) (PEG) and an acid‐labile polycarbonate, poly(2,4,6‐trimethoxybenzylidenepentaerythritol carbonate)‐based polymersomes were used to encapsulated hydrophobic paclitaxel and hydrophilic doxorubicin hydrochloride simultaneously 39,40 .…”