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PH-Induced Transformation of Biodegradable Multilamellar Nanovectors for Enhanced Tumor Penetration.

ABSTRACT: Herein we describe biodegradable nanovectors comprised of block copolymers of poly(ethylene glycol) and poly(trimethylene carbonate) (PEG-PTMC) that change their morphology and surface charge when exposed to tumor environment conditions. Well-defined, drug-loaded nanovectors were prepared via direct hydration using liquid oligo(ethylene glycol) as a dispersant. Systematic introduction of basic imidazole-functional TMC derivatives, through modular polymerization, resulted in polymers that self-assembled in multilamellar nanoparticles (at neutral pH) and that were loaded with hydrophobic drugs. The resultant multilamellar nanovectors demonstrated a significant size reduction and charge reversal at pH ? 6.5, which yielded cationic nanovectors that were tailored for tumor penetration. In vitro studies using 3D heterospheroids demonstrate that this platform has excellent potential to promote enhanced tumor penetration under physiological conditions.

SUBMITTER: Cao S

PROVIDER: S-EPMC6281313 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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pH-Induced Transformation of Biodegradable Multilamellar Nanovectors for Enhanced Tumor Penetration.

Cao Shoupeng S Abdelmohsen Loai K E A LKEA Shao Jingxin J van den Dikkenberg Joep J Mastrobattista Enrico E Williams David S DS van Hest Jan C M JCM

ACS macro letters 20181112 11

Herein we describe biodegradable nanovectors comprised of block copolymers of poly(ethylene glycol) and poly(trimethylene carbonate) (PEG-PTMC) that change their morphology and surface charge when exposed to tumor environment conditions. Well-defined, drug-loaded nanovectors were prepared via direct hydration using liquid oligo(ethylene glycol) as a dispersant. Systematic introduction of basic imidazole-functional TMC derivatives, through modular polymerization, resulted in polymers that self-as ...[more]

PMID: 30533279

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Project description:Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.

Project description:BackgroundOncolytic viruses are among the most powerful and selective cancer therapeutics under development and are showing robust activity in clinical trials, particularly when administered directly into tumor nodules. However, their intravenous administration to treat metastatic disease has been stymied by unfavorable pharmacokinetics and inefficient accumulation in and penetration through tumors.MethodsAdenovirus (Ad) was "stealthed" with a new N-(2-hydroxypropyl)methacrylamide polymer, and circulation kinetics were characterized in Balb/C SCID mice (n = 8 per group) bearing human ZR-75-1 xenograft tumors. Then, to noninvasively increase extravasation of the circulating polymer-coated Ad into the tumor, it was coinjected with gas microbubbles and the tumor was exposed to 0.5 MHz focused ultrasound at peak rarefactional pressure of 1.2 MPa. These ultrasound exposure conditions were designed to trigger inertial cavitation, an acoustic phenomenon that produces shock waves and can be remotely monitored in real-time. Groups were compared with Student t test or one-way analysis of variance with Tukey correction where groups were greater than two. All statistical tests were two-sided.ResultsPolymer-coating of Ad reduced hepatic sequestration, infection (>8000-fold; P < .001), and toxicity and improved circulation half-life (>50-fold; P = .001). Combination of polymer-coated Ad, gas bubbles, and focused ultrasound enhanced tumor infection >30-fold; (4 × 10(6) photons/sec/cm(2); standard deviation = 3 × 10(6) with ultrasound vs 1.3 × 10(5); standard deviation = 1 × 10(5) without ultrasound; P = .03) and penetration, enabling kill of cells more than 100 microns from the nearest blood vessel. This led to substantial and statistically significant retardation of tumor growth and increased survival.ConclusionsCombining drug stealthing and ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of metastatic cancer.

Dataset Information

PH-Induced Transformation of Biodegradable Multilamellar Nanovectors for Enhanced Tumor Penetration.

Publications

pH-Induced Transformation of Biodegradable Multilamellar Nanovectors for Enhanced Tumor Penetration.

Similar Datasets

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