Biopolymeric Prodrug Systems as Potential Antineoplastic Therapy

Abstract

Nowadays, cancer represents a major public health issue, a substantial economic issue, and a burden for society. Limited by numerous disadvantages, conventional chemotherapy is being replaced by new strategies targeting tumor cells. In this context, therapies based on biopolymer prodrug systems represent a promising alternative for improving the pharmacokinetic and pharmacologic properties of drugs and reducing their toxicity. The polymer-directed enzyme prodrug therapy is based on tumor cell targeting and release of the drug using polymer-drug and polymer-enzyme conjugates. In addition, current trends are oriented towards natural sources. They are biocompatible, biodegradable, and represent a valuable and renewable source. Therefore, numerous antitumor molecules have been conjugated with natural polymers. The present manuscript highlights the latest research focused on polymer-drug conjugates containing natural polymers such as chitosan, hyaluronic acid, dextran, pullulan, silk fibroin, heparin, and polysaccharides from Auricularia auricula.

Keywords: Auricularia auricula polysaccharides; PDEPT; antineoplastic therapy; biopolymer; chitosan; dextran; heparin; hyaluronic acid; prodrug systems; pullulan; silk fibroin.

Figure 6

Drug–hyaluronic acid conjugates; (a) HA-amino acid-PTX conjugate [119]; (b) HA-DTX [125]; (c) HA-5-FU adapted after [129]. 5-FU—5-fluorouracil; AA—amino acid; DTX—docetaxel; HA—hyaluronic acid; PTX—paclitaxel.

Figure 6

Drug–hyaluronic acid conjugates; (a) HA-amino acid-PTX conjugate [119]; (b) HA-DTX [125]; (c) HA-5-FU adapted after [129]. 5-FU—5-fluorouracil; AA—amino acid; DTX—docetaxel; HA—hyaluronic acid; PTX—paclitaxel.

Figure 1

Stages in PDEPT and PELT strategies: 1—administration of polymer–drug/lipid–drug conjugate; 2—administration of polymer–enzyme conjugate; 3—intratumoral drug release. Adapted from [22], Elsevier, 2017.

Figure 2

Improved properties of polymer–drug conjugate [8,22].

Figure 3

Examples of doxorubicin and HPMA conjugates: (a) PK1; (b) PK2. Adapted from [35], published by RSC, 2019. DOX—doxorubicin; Gly-Phe-Leu-Gly—glycine–phenylalanine–leucine-glycine linker; HPMA—hydroxypropyl methacrylate.

Figure 4

Mechanism of endocytosis of drug–polymer conjugates mediated by folate receptors. 1—drug–polymer conjugation; 2—FR binding; 3—membrane invagination; 4—endocytosis; 5—drug release; 6—DNA targeting; 7—FR externalization [69,70].

Figure 5

Nanoassembly of fluorescent protein−CTS Cas9/sgRNA and gene−donor. Adapted from [101], MDPI, 2020.

Figure 7

Irinotecan and 5-FU co-loaded nanoparticles [135]. 5-FU—5 fluorouracil; HA—hyaluronic acid; PLGA—poly(D,L-lactide-co-glycolide).

Figure 8

Dextran conjugates: (a) DEX–PTX conjugate [151] and (b) DEX–MTX conjugate [152]. DEX—dextran; Gly—glycine; Ile—isoleucine; Leu—leucine; MTX—methotrexate; Pro—proline; PTX—paclitaxel; Val—valine.

Figure 9

DSPION nanoparticles with dextran and doxorubicin: (1)—DOX-Fe²⁺ loading; (2)—DOX releasing. Adapted from [158], Elsevier, 2008.

Figure 10

Doxorubicin–PDTC co-loaded nanoparticles. Adapted from [178], published by J Mater Chem B, 2015. ADH—adipohydrazide; DOX—doxorubicin; PDTC—pyrrolidine dithiocarbamate; PL—pullulan.

Figure 11

Doxorubicin–sorafenib co-loaded nanoparticles and their synergic mechanism of action [179,182] DOX—doxorubicin; FGFR1—fibroblast growth factor receptors; KIT—tyrosine-protein kinase; PDGFR1—platelet-derived growth factor receptors; PL—pullulan; VEGFR—vascular endothelial growth factor. 1—doxorubicin-pullulan conjugation; 2—self-assembly of the NP with sorafenib; 3—membrane invagination; 4—endocytosis; 5—drug release; 6—DNA targeting.

Figure 12

Pullulan–doxorubicin conjugate [194]. DOX—doxorubicin; PL—pullulan.

Figure 13

Heparin–folic acid–PTX conjugate [216].

Figure 14

FA-AAP-CDDP polymeric complex.