Improving Paclitaxel Delivery: In Vitro and In Vivo Characterization of PEGylated Polyphosphoester-Based Nanocarriers

Abstract

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 μg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

“…For drug delivery applications, poly(phosphoesters) can be copolymerized with polyethers and polyesters, and they are gaining attention as biomaterials. 196,199–202 …”

Carrier-free, self-assembled pure drug nanorods composed of 10-hydroxycamptothecin and chlorin e6 for combinatorial chemo-photodynamic antitumor therapy in vivo

“…3–7 Recent years, nanomedicine has emerged as an innovative and promising strategy for more effective and safer cancer treatment. 8–11 Tremendous attention has been paid to develop various kinds of nanoscale drug delivery systems (nDDS), such as liposomes, 12–15 dendrimers, 16–18 micelles, 19–23 inorganic nanomaterials, 24–30 and so on. Two main approaches have been employed to prepare nanoformulations of anticancer drugs, including directly encapsulating drugs with nanocarriers and conjugating drugs to macromolecular nanovectors.…”

Polymeric Nanostructures for Imaging and Therapy

“…237-238 The design and development of well-defined polymer-based nanodelivery systems, with control over their composition, structure and morphology, is expected to provide for ultra-high drug loading within intact nanoparticles, followed by sustained release, facilitated by optimized biodistribution and polymer degradation, and timed to the rate of disease progression. 140 …”

“…140,240,319-321 Hierarchically-assembled theranostic (HAT) nanostructures based on anionic shell crosslinked rod-like nanoparticles and cationic spherical SCKs have recently been developed by our group to deliver siRNA intracellularly, and to undergo radiolabeling. 319 In addition, paclitaxel, a hydrophobic anticancer drug, and siRNA have been successfully loaded into the cylindrical and spherical components of the hierarchical assemblies, respectively (Figure 30).…”