Polyprodrug Amphiphiles: Hierarchical Assemblies for Shape-Regulated Cellular Internalization, Trafficking, and Drug Delivery

Abstract

Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.

Controlling the morphology of copolymeric vectors for next generation nanomedicine

“…Such changes in the morphological properties of NVs would facilitate a concomitant activation or release of functional cargo in order to address the particular diseased tissue and, as such, have great clinical potential [43]. Another approach to stimuli-responsive selectivity is to programme the release of functional components as a result of changes in the local environment such as redox or pH-induced cleavage of drug-polymer scaffolds [25,44] or pHinduced charge reversal leading to release of siRNA [44].…”

“…Although morphological features such as rigidity, size and surface charge can be introduced through well-established means and methodologies, the ability to control shape of BCP architectures can be a much more challenging prospect. Utilising changes in the structure of BCPs, and the conditions in which they are assembled, it is possible to controllably direct the formation of spherical or worm-like micelles, vesicles and assorted compound structures [25,60] where fine control of the balance between the hydrophilic and hydrophobic components is of critical importance. Worm-like micellar NVs, so-called 'filomicelles' named by analogy with filoviruses, are composed of PEG-polylactide copolymers that are assembled through dissolution in organic solvent and subsequent dispersion in an aqueous solution with evaporation of the volatile organics yielding the desired NVs [20,61].…”

“…In other studies, it has been demonstrated that excessive particle stiffness can impede cellular uptake [13] and it is possible to add cholesterol, a ubiquitous plasticizer of biological membranes, to a polymersome in order to enhance uptake [74]. Enhanced cellular uptake has also been demonstrated as a consequence of imbuing NVs with non-spherical shapes, which needs to be investigated more extensively in order to give more extensive understanding [25]. Moreover, particle shape has been identified as a critical factor in particle uptake by phagocytes, with non-spherical morphologies giving rise to a range of behaviours [75,76].…”

“…The value of stealth behaviour for the circulation of polymeric NPs has been welldocumented and is a consequence of the protective layer of hydrophilic polymers on the particle surface [24]. BCP NPs with other morphological characteristics such as discs, compound vesicles and staggered lamellae are also being developed for drug delivery applications and have demonstrated morphology dependant cellular internalization and blood circulation [25].…”

Novel walnut peptide–selenium hybrids with enhanced anticancer synergism: facile synthesis and mechanistic investigation of anticancer activity

“…[6][7][8][9][10] It is well documented that nanoparticle-based drugs have many advantages including targeted However, precisely controlling the grain/particle size, modulating the surface properties, increasing the stability, and neutralizing the toxicity/hazards are the major challenges in the synthesis as well as in application of drug-loaded nanomaterials for therapeutic applications. 12,13 Selenium (Se) is an essential trace element with unique physiological and pharmacological properties. 14,15 Many studies have demonstrated that supplemental Se uptake can reduce several disease risks including cancers, muscle disorders, diabetes mellitus, and cardiovascular diseases.…”