Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Dec 1;30(Pt B):318-330.
doi: 10.1016/j.jddst.2015.05.012.

POLYMERIC BIOMATERIALS AND NANOMEDICINES

Jiyuan Yang  1 , Jindřich Kopeček  2
Affiliations

POLYMERIC BIOMATERIALS AND NANOMEDICINES

Jiyuan Yang et al. J Drug Deliv Sci Technol. .

Abstract

This overview intends to demonstrate the close relationship between the design of smart biomaterials and water-soluble polymer-drug conjugates. First, the discovery and systematic studies of hydrogels based on crosslinked poly(meth)acrylic acid esters and substituted amides is described. Then, the lessons learned for the design of water-soluble polymers as drug carriers are highlighted. The current state-of-the-art in water-soluble, mainly poly[N-(2-hydroxypropyl)methacylamide (HPMA), polymer-drug conjugates is shown including the design of backbone degradable HPMA copolymer carriers. In the second part, the modern design of hybrid hydrogels focuses on the self-assembly of hybrid copolymers composed from the synthetic part (backbone) and biorecognizable grafts (coiled-coil forming peptides or morpholino oligonucleotides) is shown. The research of self-assembling hydrogels inspired the invention and design of drug-free macromolecular therapeutics - a new paradigm in drug delivery where crosslinking of non-internalizating CD20 receptors results in apoptosis in vitro and in vivo. The latter is mediated by biorecognition of complementary motifs; no low molecular weight drug is needed.

Keywords: Cancer; Drug-free macromolecular therapeutics; Hydrogels; Nanomedicines; Polymer-drug conjugates; Self-assembly of macromolecules.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The use of HEMA-based hydrogels (copolymers of HEMA with EDMA) in rhinoplasty. A) Patient before surgery; B) Patient after surgery. Reprinted from reference with permission.
Figure 2
Figure 2
Tumor growth inhibition by P-CYP, P-DTX, and combination of P-DTX and P-CYP in PC-3 tumor-bearing nude mice. Data are presented as mean±SD. Reprinted from reference with permission.
Figure 3
Figure 3
Combination treatment of 2nd generation conjugates showed improved therapeutic efficacy in A2780 human ovarian carcinoma xenografts. (A) Blood activity-time profiles of 125I-labeled conjugates in mice. The data represent the mean radioactivity expressed as a percentage of the injected dose per gram of blood from mice (n=5). (B) SPECT/CT images of mice bearing subcutaneous A2780 human ovarian carcinoma in right flank after intravenous injection of 125I-labeled conjugates (2P-PTX, 2P-GEM). The representative images were acquired 24 h, 48 h, and 7 d after administration of conjugates. T, tumor. (C) Experimental schedules of treatment in mice bearing A2780 human ovarian tumor xenografts. Female nude mice received one dose of PTX or HPMA copolymer-PTX conjugate (20 mg/kg PTX equivalent) on day 0 and 3 doses of GEM or HPMA copolymer-GEM conjugate (5 mg/kg GEM equivalent) on days 1, 7, and 14. (D) A2780 tumor growth in mice treated with different formulation combinations (n=5). * p<0.01. Note: in the orange (2P-PTX→2P-GEM) line the error bars are hidden within the experimental points. (E) Photographs of A2780 tumors after treatment with different combinations. Reprinted from reference with permission.
Figure 4
Figure 4
Percentage of bone mineral density increase in OVX Sprague-Dawley rats following administration of Asp8-targeted HPMA copolymer–PGE1 conjugates. The BMD was measured on day -2 and day 33. Left columns – untreated controls (saline); middle columns - P-Asp8-PGE1 (1st generation conjugate, Mw 51.2 kDa); right columns - mP-Asp8-PGE1 (2nd generation multiblock backbone degradable conjugate, Mw 329 kDa). * P < 0.05 for mP-Asp8-PGE1 group compared to control. **P < 0.05 for mP-Asp8-PGE1 group compared to P-Asp8-PGE1 and control. n = 5 per group. Data are means ± SD. Reprinted from reference with permission.
Figure 5
Figure 5
A) The structure of the HPMA copolymer – 9-AC conjugate (P-9-AC). B) Survival curves of mice bearing human colon carcinoma xenografts treated by 9-AC and P-9-AC at a dose of 3 mg/kg of 9-AC or 9-AC equivalent. Reprinted from reference with permission.
Figure 6
Figure 6
Therapeutic efficacy of drug-free macromolecular therapeutics based on coiled-coil peptides against systemically disseminated Raji B cell lymphoma in C.B.-17 SCID mice (7 mice per group). A) Top panel shows timeline for the in vivo efficacy study. Four million Raji B cells were injected into the tail vein on day 0 to initiate the disseminated disease. The incidence of hind-limb paralysis or survival of mice was monitored until day 100. Five groups of animals were evaluated: untreated controls; consecutive administration of single dose (CS); premixed administration of single dose (PS); consecutive administration of three doses at days 1, 3, and 5 (CM); and premixed administration of three doses at days 1, 3, and 5 (PM). Consecutive administration involved the i.v. injection of 50 µg/20 g Fab’-CCE first and 1 h later the i.v. administration of 324 µg/20 g CCK-P conjugate; for premixed administration, the two conjugates were mixed together 1 h before injection via the tail vein. Bottom panel shows survival rate of tumor-bearing mice that received above treatments. The curve was presented in a Kaplan-Meier plot with indication of numbers of long-term survivors (7 mice per group); B) Estimation of residual Raji B lymphoma cells in the bone marrow. Shown are results from representative mice that received the indicated treatment. Revealed are histograms of bone marrow cells isolated from mice (as indicated) followed by staining with PE mouse anti-human CD10 and APC mouse anti-human CD19. Reprinted from reference with permission.
Figure 7
Figure 7
In vivo efficacy of drug-free macromolecular therapeutics based on morpholino oligonucleotides against systemic B-cell lymphoma. SCID mice were injected with luciferase-expressing Raji cells (4 × 106) via the tail vein on day 0. Three doses of each treatment were administered on days 7, 9, and 11. PBS: mice injected with PBS (n = 6); Cons 1h: consecutive treatment of Fab'-MORF1 and P-MORF2, 1 h interval (n = 7); Cons 5h: consecutive treatment of Fab'-MORF1 and P-MORF2, 5 h interval (n = 6); Rituximab (n = 6); 1F5 mAb (n = 6). (A) Paralysis-free survival of mice presented in a Kaplan-Meier plot. Numbers of long-term survivors in each group are indicated. Statistics was performed with log-rank test (*: p < 0.05, **: p < 0.005, n.s.: no significant difference). (B) In vivo bioluminescence images at 25 days post-tumor injection. Mice were i.p. injected with 3 mg firefly D-luciferin 15 min prior imaging. (C) Whole-body bioluminescence intensity of mice. Data are shown as mean ± SEM (n = 6 or 7). Statistics was performed by student’s t test (**: p < 0.005). Black arrow: dose administration. Reprinted from reference with permission.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wichterle O, Lím D. Hydrophilic gels for biological use. Nature. 1960;185:117–118.
    1. Kopeček J. Hydrogels: From soft contact lenses and implants to self-assembled nanomaterials. J. Polym. Sci.: Part A: Polym. Chem. 2009;47:5929–5946. - PMC - PubMed
    1. Wichterle O. (Czechoslovak Academy of Sciences), U.S. Patents 3,660,545; 3,408,429; 3,496,254; 3,499,862.
    1. Kopeček J, Šprincl L. Relationship between the structure and biocompatibility of hydrophilic gels. Polim. Med. 1974;4:109–117. - PubMed
    1. Kopeček J, Yang J. Smart self-assembled hybrid hydrogel biomaterials. Angew. Chem. Int. Ed. 2012;51:7396–7417. - PMC - PubMed

LinkOut - more resources