Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small-molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water-soluble agents, and (iii) selectively targeting specific tissues. Although several polymerbased systems have addressed the first two demands and have been translated into clinical practice, no targeted synthetic drug delivery system has reached the market. This Review is designed to provide a background on the challenges and requirements for the design and translation of new polymer-based delivery systems. This report will focus on chemical approaches to drug delivery for systemic applications.
In
this paper, we present well-defined dPGS-SS-PCL/PLGA/PLA micellar
systems demonstrating excellent capabilities as a drug delivery platform
in light of high stability and precise in vitro and in vivo drug release combined with active targetability
to tumors. These six amphiphilic block copolymers were each targeted
in two different molecular weights (8 or 16 kDa) and characterized
using 1H NMR, gel permeation chromatography (GPC), and
elemental analysis. The block copolymer micelles showed monodispersed
size distributions of 81–187 nm, strong negative charges between
−52 and −41 mV, and low critical micelle concentrations
(CMCs) of up to 1.13–3.58 mg/L (134–527 nM). The serum
stability was determined as 94% after 24 h. The drug-loading efficiency
for Sunitinib ranges from 38 to 83% (8–17 wt %). The release
was selectively triggered by glutathione (GSH) and lipase, reaching
85% after 5 days, while only 20% leaching was observed under physiological
conditions. Both the in vitro and in vivo studies showed sustained release of Sunitinib over 1 week. CCK-8
assays on HeLa lines demonstrated the high cell compatibility (1 mg/mL,
94% cell viability, 48 h) and the high cancer cell toxicity of Sunitinib-loaded
micelles (IC50 2.5 μg/mL). By in vivo fluorescence imaging studies on HT-29 tumor-bearing mice, the targetability
of dPGS7.8-SS-PCL7.8 enabled substantial accumulation
in tumor tissue compared to nonsulfated dPG3.9-SS-PCL7.8. As a proof of concept, Sunitinib-loaded dPGS-SS-poly(ester)
micelles improved the antitumor efficacy of the chemotherapeutic.
A tenfold lower dosage of loaded Sunitinib led to an even higher tumor
growth inhibition compared to the free drug, as demonstrated in a
HeLa human cervical tumor-bearing mice model. No toxicity for the
organism was observed, confirming the good biocompatibility of the
system.
Schlechte Wasserlöslichkeit und geringe Bioverfügbarkeit von pharmazeutischen Wirkstoffen (APIs) sind die Hauptursache für Verzögerungen in der pharmazeutischen Industrie und stellen eine große Hürde für die Entwicklung neuer Arzneimittel dar. Der Transport von Arzneimitteln ist nach wie vor die größte Herausforderung für die Anwendung niedermolekularer Medikamente und Biopharmazeutika. Die drei Herausforderungen für synthetische Transportsysteme sind: (i) Kontrolle über die Wirkstoffverteilung und Clearance im Blut, (ii) Solubilisierung schlecht wasserlöslicher Wirkstoffe und (iii) selektive Akkumulation in bestimmten Geweben. Obwohl viele Polymer-basierte Systeme die ersten beiden Anforderungen erfüllen und in die klinische Praxis umgesetzt wurden, hat bisher noch kein zielgerichtetes, synthetisches Abgabesystem den Markt erreicht. Dieser Aufsatz soll einen Überblick über die Herausforderungen und Anforderungen zur Entwicklung und Umsetzung neuer Polymer-basierter Darreichungssysteme geben. Hauptaugenmerk liegt hierbei auf den chemischen Ansätzen für die Darreichung von Wirkstoffen für systemische Anwendungen.
Highly stable micelles are facilitated by π–π interactions in an amphiphilic block copolymer system consisting of dPGS-SS-POxPPh-Py, where each building block contributes a particular ability.
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