Structure-Based Varieties of Polymeric Nanocarriers and Influences of Their Physicochemical Properties on Drug Delivery Profiles

Abstract

Carriers are equally important as drugs. They can substantially improve bioavailability of cargos and safeguard healthy cells from toxic effects of certain therapeutics. Recently, polymeric nanocarriers (PNCs) have achieved significant success in delivering drugs not only to cells but also to subcellular organelles. Variety of natural sources, availability of different synthetic routes, versatile molecular architectures, exploitable physicochemical properties, biocompatibility, and biodegradability have presented polymers as one of the most desired materials for nanocarrier design. Recent innovative concepts and advances in PNC-associated nanotechnology are providing unprecedented opportunities to engineer nanocarriers and their functions. The efficiency of therapeutic loading has got considerably increased. Structural design-based varieties of PNCs are widely employed for the delivery of small therapeutic molecules to genes, and proteins. PNCs have gained ever-increasing attention and certainly paves the way to develop advanced nanomedicines. This article presents a comprehensive investigation of structural design-based varieties of PNCs and the influences of their physicochemical properties on drug delivery profiles with perspectives highlighting the inevitability of incorporating both the multi-stimuli-responsive and multi-drug delivery properties in a single carrier to design intelligent PNCs as new and emerging research directions in this rapidly developing area.

Keywords: multi-drug delivery; multi-stimuli-responsive; nanomaterials; polymers; self-assembly.

Figure 1

a) A schematic presentation overviewing variety, property, applications, and future perspectives of polymeric nanocarriers discussed in this study. b) Multiple steps involved in bringing a new drug into clinical practice. Abbreviations. ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity. NDA: New Drug Application. (Reproduced with permission from Enzo Life Sciences. Innovative Tools for Accelerating Drug Discovery. Retrieved from https://www.enzolifesciences.com/browse/drug‐discovery/).

Figure 2

a) Number of articles published per year on various polymeric carriers (Database: Scopus. Keywords used for the searches: “drug delivery system” + “polymer” and then each of the following nanocarriers, “nanocomposite;” “dendrimer;” “nanogel;” “nanosphere;” “nanocapsule;” “polymersome;” “nanomicelle”). b) Size ranges of various polymeric nanocarriers (PNCs). c) Various anatomic routes for drug administration. Reproduced with permission.^{[ 103 ]} Copyright 2018, Elsevier. Reproduced with permission from National institute of general medical sciences image., A drug's life in the body (without labels), https://images.nigms.nih.gov/Pages/DetailPage.aspx?imageID2=2527, accessed date: 9 January 2022. d) Examples of major routes for drug administration.

Figure 3

a) Architecture‐based variety of polymeric nanocarriers employed in delivering various types of therapeutics. b) Schematic presentation of drug release from polymer nanoparticle stimulated by various physical, chemical, and biological factors.

Figure 4

Examples of some advanced applications of biodegradable polymers and their nanostructures in disease treatment.

Figure 5

a) Various polymeric nanomicelles that can be fabricated depending on the architectures of copolymers and inter‐chain interactions. b) Schematic presentation of a wormlike micelle having hydrophobic core surrounded by hydrophilic blocks of amphiphilic polymers. Reproduced with permission.^{[ 167 ]} Copyright 2003, American Chemical Society. c) Intracellular pH‐activated drug release from wormlike micelle composed of dye‐tagged diblock copolymer poly(ethylene glycol)‐b‐poly(2‐diisopropyl methacrylate)‐tetramethyl rhodamine (mPEG‐b‐PDPA‐TMR). Reproduced with permission.^{[ 168 ]} Copyright 2010, Royal Society of Chemistry. d) Concentration dependent self‐assembly mechanism of micelle formation composed of triblock biodegradable copolymer poly(ethylene glycol)‐b‐1,3‐bis(p‐carboxyphenoxy) propane‐b‐sebacic acid (PEG‐b‐CPP‐b‐SA). Abbreviation. DOX.HCl: Doxorubicin hydrochloride. Reproduced with permissions.^{[ 169 ]} Copyright 2005, Royal Society of Chemistry.

Figure 6

a) Schematic presentation of liposome and polymer nanovesicle. b) A novel photo‐responsive polymersome capable of co‐loading both the hydrophilic and hydrophobic drugs. Reproduced with permission.^{[ 176 ]} Copyright 2014, Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 7

a) A schematic presentation of nanogel synthesis by miniemulsion polymerization and its pH‐responsive drug release phenomena for cancer therapy. Reproduced with permission.^{[ 195 ]} Copyright 2011, Elsevier. b) Nanogel transcytosis across an in vitro blood‐brain barrier facilitated by low nanogel stiffness. Reproduced under the terms of a Creative Commons Attribution 4.0 International License.^{[ 204 ]} Copyright 2021, The Authors. ublished by Elsevier. c) The scanning electron microscopic image of T lymphocyte invading through the poly(ethylene glycol)‐g‐chitosan gel. d) Percent of tumor cell death (U‐87 MG cell line) caused by T lymphocyte treatment at various T lymphocyte/U87 ratios (1/0, 3/1, 100/1). Mock is the negative control. e) Fluorescence image of T lymphocytes (green) attached to U‐87 MG cells (red) after crossing through the transwell membrane mimicking the blood‐brain barrier under in vitro test condition. c–e) Reproduced with permission.^{[ 207 ]} Copyright 2014, American Chemical Society.

Figure 8

a) Schematic presentation of controlled insulin release from polymeric nanogel triggered by the presence of glucose. Reproduced with permission.^{[ 208 ]} Copyright 2015, Royal Society of Chemistry. b) Poly‐N‐isopropyl acrylamide‐based nanogel as double‐stimuli‐responsive (temperature and pH) drug carrier. Reproduced under the terms of a Creative Commons Attribution 4.0 International License.^{[ 209 ]} Copyright 2019, The Authors. Published by Springer Nature.

Figure 9

a) Nanocapsule having polymeric shell and liquid core with encapsulated drug molecules. b) Schematic illustration of polymeric nanocapsules and their use in various bioapplications.^{[ 220 ]} Protein image (1HFW) is from protein data bank (https://www.rcsb.org/structure/1HFW). c) Design strategy and anticancer drug delivery mechanism of reducing agent glutathione responsive pillar[5]arene‐based single molecular layer polymer nanocapsule demonstrating the targeted delivery. Reproduced with permission.^{[ 221 ]} Copyright 2018, American Chemical Society.

Figure 10

a) Vast application field of dendrimer‐based nanocarriers in drug delivery. Reproduced with permission.^{[ 222 ]} Copyright 2013, Elsevier. b) The synthetic route of dual‐targeting drug carrier polyamidoamine‐poly(ethylene glycol)‐wheat germ agglutinin‐transferrin‐doxorubicin (PAMAM‐PEG‐WGA‐Tf‐DOX). Reproduced with permission.^{[ 243 ]} Copyright 2010, Elsevier.

Figure 11

a) Stimuli‐responsive in vivo degradation of dendrimer. b) Schematic presentation of biodegradation of a biodegradable dendrimer. Reproduced with permission.^{[ 245 ]} Copyright 2018, Elsevier.

Figure 12

a) Percent internalization of particles having different aspect ratio in HeLa cells. Legends present particle diameter per volume. Reproduced with permission.^{[ 246 ]} Copyright 2008, The National Academy of sciences of the USA. b) Influence of molecular weight of polyethylene glycol on the size of nanocarriers. Reproduced with permission.^{[ 249 ]} Copyright 2019, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. c) Fate of nanocarriers depending upon their size, shape, surface charge, and modifications. In general, rod‐shaped nanocarriers extravasate while spherical and larger nanocarriers continue in the circulatory track (top left); nanocarriers having positive surface charge and the ones whose surface are uncoated/modified get cleared out faster by macrophages (top right); neutral, rod‐shaped and targeted nanocarriers can easily permeate tumor showing better local distribution (bottom left) whereas carriers that are smaller, coated, and surface with positive charge can permeate mucosal barriers more easily (bottom right). Reproduced with permission.^{[ 1 ]} Copyright 2020, Springer Nature.

Figure 13

a) A schematic presentation of multi‐stimuli‐responsive biohybrid polymeric nanocarrier. The nanocarrier is responsive to physical, chemical, and biological stimuli. Reproduced with permission.^{[ 269 ]} Copyright 2017, Elsevier. b) Design strategies of a few representative PNCs for multi‐drug delivery. Various types of drug molecules can be loaded on a carrier based on the properties of polymer blocks.

Figure 14

An overview on the work progress in multi‐stimuli‐responsive and multi‐drug‐delivery polymeric nanocarrier design. The literature searches were carried out in Scopus database. Keywords used for the searches are “polymer” + “multi‐stimuli‐responsive” and “polymer” + “multi‐drug‐delivery.”