Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications

Abstract

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 polymer-based 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.

Keywords: Drug Delivery Systems; PEGylation; Polymer-Drug Conjugates; Polymer-Protein Conjugates; Self-Assembled Systems.

Figure 1

Overview of PEG‐alternative macromolecules for protein and drug conjugation: poly(ethylene glycol) (PEG), linear polyglycerol (LPG), poly(2‐oxazoline) (POx), polycarboxybetaines (PCB), polysulfobetaines (PSB), poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC), polyglutamic acid (PGA), polysarcosine (PSar), poly(N‐(2‐hydroxypropyl) methacrylamide) (PHPMA), and polysialic acid (PSA).

Figure 2

Conceptual scheme of the Ringsdorf model.

Figure 3

Chemical structure of AZD0466 and dendrimer‐AZD4320 conjugates showing the dendrimer structure of PEGylated PLL and the linkers used. Adapted from Ref. .

Figure 4

Architectures and categories of supramolecular drug delivery systems.

Figure 5

The different physical behavior of unimolecular and polymeric micelles upon degradation and drug release.

Figure 6

Overview of synthetic approaches towards amphiphilic block copolymers and the most frequently used monomers.

Figure 7

Overview of polymer–drug conjugate block copolymer micelles that reached clinical trials.

Figure 8

Overview of synthetic approaches for the introduction of targeting ligands onto amphiphilic block copolymers.

Figure 9

The concept of charge conversion of biomacromolecules to improve their therapeutic efficacy.