Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer

Abstract

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination (“EP/PE”) therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles

“…More recently, poly(2-oxazine)s, their higher main-chain homologues have also raised some interest [24][25][26][27]. In fact, POx based amphiphiles have high potential for drug formulation development, demonstrated in various tumor models [28][29][30][31][32][33]. Luxenhofer and coworkers reported an ultra-high paclitaxel (PTX) loaded POx based micellar formulation (loading capacity (LC) ≈ 50 wt.% (m Drug /(m Drug +m Polymer )) [34] with excellent in vivo anti-tumor efficacy [29,30].…”

Interplay of Solvation and Size Effects Induced by the Counterions in Ionic Block Copolymers on the Basis of Hofmeister Series

“…The self‐assembly of amphiphilic block copolymers (BCPs) in selective solvents is increasingly attracting the attention of researchers in the past decades due to their potential applications in biological drug delivery, microreactor chemistry, and in novel nanostructural templating . In selective solvents, neutral BCPs can form various morphologies such as spheres, cylinders, vesicles, and lamellae, which can be regulated by many factors, such as block length, solvent composition, pH, and inorganic salt . Self‐assembly behaviors of these BCPs are well documented …”

Co-delivery of dihydroartemisinin and docetaxel in pH-sensitive nanoparticles for treating metastatic breast cancerviathe NF-κB/MMP-2 signal pathway

“…5,6 One of the most established technologies of drug delivery is the use of nanoscale delivery vehicles such as liposomes and nanoparticles for cancer therapy, which afford efficient accumulation of drugs at the tumor sites by exploiting the pathological characteristics of tumors like enhanced permeability and retention (EPR). 7 However, the therapeutic efficacy of some nanoscale delivery vehicles is suboptimal, mainly because of inefficient drug loading, short lifetime and inability to release drugs at specic sites. 8 Therefore, a drug delivery system that allows high drug loading, long lifetime and site-specic drug release in the tumor environment is highly desirable.…”