Cancer Nanomedicines Stabilized by π-π Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations

Abstract

Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular π-π stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self-assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles.

Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer

“…Finally, Cy5.5-labeled theranostic self-assembled supramolecular NPs stabilized by PEGylated phospholipids and including two chemotherapeutic agents in the form of prodrugs have been demonstrated to be effective imaging and therapeutic agents in a colorectal carcinoma mouse model. 13 All these systems demonstrate the potential of theranostic nanomedicines. Our system, however, provides the means for imaging contrast to be activated at the tumor site, which is expected to provide significant increase in tumor signal:background ratio.…”

“…5 For this reason, efforts to develop alternative chemotherapy treatments have focused on designing nanoscale agents that are more specific against cancer cells to minimize toxic side effects and improve therapeutic efficacy. [6][7][8][9][10][11][12][13] The use of nanoscale agents enhances tumor selectivity via passive and active targeting. 14 The combination of therapeutic and diagnostic agents within a single nanoscale "theranostic" platform offers significant potential to make personalized nanomedicine a clinical reality for cancer patients.…”

Stimuli‐responsive nanotherapeutics for precision drug delivery and cancer therapy

“…The aim of chemotherapy is to improve the survival time and life quality for cancer patients; therefore, increasing drug tolerability as well as therapeutic efficacy in patients can be accomplished by optimizing the physiochemical property of administered drugs. Within this context, nanoparticle‐mediated DDSs have emerged to hold the potential to mitigate these obstacles (Wang et al, , ). In addition to enhanced drug solubility and stability, this approach has the ability to specifically transport chemotherapeutics to target cancer cells while preventing adverse effects on healthy organs and tissues (Byrne, Betancourt, & Brannon‐Peppas, ; Xu et al, ).…”

Polylactide-tethered prodrugs in polymeric nanoparticles as reliable nanomedicines for the efficient eradication of patient-derived hepatocellular carcinoma

“…Nanomedicines that achieve long-term systemic circulation and appropriate particle sizes (typically smaller than 200 nm) are expected to passively accumulate in the target solid tumors because of the leaky and disorganized tumor vasculature, coupled with impaired tumor lymphatic drainage 15 . Such structural and functional abnormalities can produce enhanced permeability and retention (EPR), thus potentiating the therapeutic efficacy of nanomedicines relative to that of free drugs in numerous preclinical animal models 16 , 17 . Physically entrapping therapeutic molecules into polymer matrices via a simple self-assembly process has been actively explored for the construction of nanoscopic objects for precise drug delivery 18 - 23 .…”