Functionalized Particles Designed for Targeted Delivery

Abstract

Pure bioactive compounds alone can only be exceptionally administered in medical treatment. Usually, drugs are produced as various forms of active compounds and auxiliary substances, combinations assuring the desired healing functions. One of the important drug forms is represented by a combination of active substances and particle-shaped polymer in the nano- or micrometer size range. The review describes recent progress in this field balanced with basic information. After a brief introduction, the paper presents a concise overview of polymers used as components of nano- and microparticle drug carriers. Thereafter, progress in direct synthesis of polymer particles with functional groups is discussed. A section is devoted to formation of particles by self-assembly of homo- and copolymer-bearing functional groups. Special attention is focused on modification of the primary functional groups introduced during particle preparation, including introduction of ligands promoting anchorage of particles onto the chosen living cell types by interactions with specific receptors present in cell membranes. Particular attention is focused on progress in methods suitable for preparation of particles loaded with bioactive substances. The review ends with a brief discussion of the still not answered questions and unsolved problems.

Keywords: functional polymer; microparticle; nanoparticle; nucleic acid; polymerosome; protein; targeted drug delivery.

Scheme 1

Order of resistance of chemical linkages toward hydrolysis.

Scheme 2

Degradation of polyanhydrides by hydrolysis.

Scheme 3

Amphiphilic copolymers with poly(ethylene oxide) and poly(1,3-bis(p-carboxyphenoxy)propane) or poly(1,6-bis(p-carboxyphenoxy) hexane) blocks.

Scheme 4

Structures of five- and six-membered carbonates and polymers obtained by their ROP processes (based on data from References [51,56]).

Scheme 5

Hydrolysis of poly(trimethylene carbonate) (based on data from Reference [50]).

Scheme 6

Degradation of poly(trimethylene carbonate) by depolymerization (based on data from Reference [56]).

Scheme 7

Structure units of polyesters commonly used for preparation of drug nanocarriers. Terminology of polylactide structure units is based on IUPAC recommendations [88].

Scheme 8

Structures of five major classes of polyorthoesters (POE) for medical applications [106,107,108].

Scheme 9

Schematic illustration of hydrolysis of polyorthoesters (A)—Class POE V, (B)—Class POE I.

Scheme 10

Degradation and chain reshuffling and repolymerization: (A)—activation of chain end-groups by proton transfer, (B)—formation of chains with active end-groups by chain scission, (C)—depolymerization by unzipping of chains with anionic end-groups, (D)—repolymerization of alkylcyanoacrylates initiated with hydroxide anions.

Scheme 11

Enzymatic hydrolysis of ester groups in poly(alkylcyanoacrylates).

Scheme 12

Structures of natural polysaccharides commonly used for fabrication of drug carriers.

Figure 1

Arrangements of amphiphilic block copolymers in liposome (or polymersome), cubosome, and hexosome type particles. Particle morphology depends on symmetry/asymmetry of hydrophilic/hydrophobic parts [156].

Scheme 13

Structure of bifunctional triblock polyester copolymers used for formation of nano- and microparticles.

Scheme 14

Structure of triblock copolymer containing poly(ethylene oxide) side blocks linked to poly(β-amino ester) with cholesterol labels via the pH sensitive linkers.

Scheme 15

Stabilization of microparticles from Pull-b-PVP copolymer with oxidized hydroxyl groups by crosslinking using cystamine dihydrochloride.

Scheme 16

Schematic illustration of formation of nanoparticles loaded with doxorubicin by self-assembly of FA-PMgDP copolymer. Explanations are in text.

Scheme 17

Reactions yielding silica particles with bromine containing ATRP initiating groups.

Scheme 18

Reactions involved in a process leading to silica particles with RAFT chain transfer groups.

Scheme 19

Reactions involved in a process used for production of gold coated with silica nanoparticles with polymer shells containing alkyne groups.

Scheme 20

Functionalization of magnetic Fe₃O₄ nanoparticles introducing epoxide groups.

Scheme 21

Functionalization of negatively charged PLGA nanoparticles by adsorption of chitosan bearing folic acid moieties.

Scheme 22

Functionalization of nanoparticles by lisozyme adsorption (TCEP denotes tris(2-carboxyethyl)phosphine buffer).

Scheme 23

Synthesis of nanoparticles bearing bromoisobutyryl bromide moiety (ATRP initiator).

Scheme 24

Preparation of functionalized particles by adsorption of streptavidin and complex formation between streptavidin and biotin.

Scheme 25

Synthesis of dopamine-poly(mannose labeled acrylate)-b-poly(Rhodamine B labeled acrylamide). Reproduced with permission from Reference [221].

Scheme 26

Schematic illustration of magnetic Fe₃O₄ nanoparticles with dopamine-poly(mannose labeled acrylate)-b-poly(rhodamin B labeled acrylamide). Reproduced with permission from Reference [221].

Scheme 27

Reactions responsible for tethering of compounds with (a) thiol or (b) amine groups to polydopamine film.

Scheme 28

Schematic illustration of PLGA particles with carboxyl groups.

Scheme 29

Schematic illustration of PLGA particles with hydroxyl groups.

Scheme 30

Reactions used for replacement of functional groups on surfaces of particles. Reaction conditions are provided in cited references: (a)—[226,227]; (b)—[228]; (c)—[229]; (d)—[230]; (e)—[216]; (f)—[231,232]; (g)—[233]; (h)—[234,235]; (i)—[212].

Scheme 31

Mono- and dual ligand gold nanoparticles targeted to cancer cells. The nanoparticles were equipped with folic acid (FA) and/or glucose (glu) ligands specifically binding corresponding receptors on the cancer cells. Upper part of the scheme presents chemical structures of FA and glu (second ligand) tethered on the gold nanoparticles with sulfide linkages. Scheme is based on data from Reference [236].

Scheme 32

Coupling of tetrazine-tagged microbubbles (Tetrazine MBs) and intravascular VEGFR2 (endothelial growth factor) receptors on tumor cells pretargeted with specific antibodies to VEGFR2, modified trans-cyclooctene (TCO). Process was developed for ultrasound molecular imaging of tumor. Membrane of microbubbles composed of streptavidin (6000 macromolecules/µm²). Scheme prepared on the basis of data in Reference [220].

Scheme 33

Tumor-targeting supramolecular nanoparticles (NPs) for PET (positron emission) imaging composed of trans-cyclooctene derivative of poly(ethylene imine) and β-cyclodextrin TCO/CD-PEI. The targeting of solid tumor eith radiolabeled ⁶⁴Cu occurs in two steps: (I) intravenous injection of SNs, followed by (II) injection of tetrazine derivative carrying ⁶⁴Cu (⁶⁴Cu-Tz). In consequence of the bioorthogonal reaction between trans-cyclooctene (from TCO/CD-PEI) and tetrazine (from ⁶⁴Cu-Tz) the conjugation of these two components takes place in vivo. The advantage of using the two-step procedure is the limit of location of radiolabeled adduct of reaction exclusive to tumor cells. The excess of unbound ⁶⁴Cu-Tz is removed with blood circulation. Figure prepared on the basis of data in Reference [237].

Scheme 34

Reactions leading to functionalization of mesoporous silica nanoparticles (MSN-NH₂) with PEG linker, followed by aza-dibenzocyclooctyne (DBCO) coupling. The reaction between DBCO-PEG-MSNs and ¹⁸F-labelled azide occurs under physiological-like conditions. The MSNs labeled with ¹⁸F were prepared for PET imaging. Scheme prepared on the basis of Reference [238].