Polymeric biomaterials and nanomedicines

Yang, Jiyuan; Kopeček, Jindřich

doi:10.1016/j.jddst.2015.05.012

Cited by 17 publications

(7 citation statements)

References 166 publications

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“…It created a bridge between the design of biomaterials and the design of nanomedicines [54]. Complementary CCK and CCE peptides that self-assemble into antiparallel coiled-coil heterodimers were engaged in the design of a new CD20 + cell apoptosis induction system, called drug-free macromolecular therapeutics [10,11].…”

Section: Discussionmentioning

confidence: 99%

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

Zhang

Fang

Yang

et al. 2017

Journal of Controlled Release

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Recently, we developed a new paradigm in macromolecular therapeutics that avoids the use of low molecular weight drugs. The activity of the “drug-free macromolecular therapeutics” is based on the biorecognition of complementary motifs at cell surface resulting in receptor crosslinking and apoptosis induction. The system is composed of two nanoconjugates: (1) a single-stranded morpholino oligonucleotide (MORF1) attached to an anti-CD20 Fab′ fragment (Fab′-MORF1); (2) multiple copies of complementary oligonucleotide MORF2 grafted to a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) – P-(MORF2)x. The two conjugates crosslink CD20 antigens via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells and induce apoptosis. Preclinical studies in a murine model of human non-Hodgkin’s lymphoma showed cancer cells eradication and long-term survivors. The aim of this study was to determine the relationship between the detailed structure of the nanoconjugates and apoptosis induction in Raji cells to allow system optimization. The factors studied include the length of the MORF sequence, the valence of P-(MORF2)x (varying x), molecular weight of P-(MORF2)x, incorporation of a miniPEG spacer between Fab′ and MORF1 and between polymer backbone and pendant MORF2, and comparison of two Fab′ fragments, one from 1F5 antibody (Fab′1F5), the other from Rituximab (Fab′RTX). The results of apoptosis induction in human Burkitt’s B-cell non-Hodgkin’s lymphoma (NHL) Raji cells as determined using three apoptotic assays (Annexin V, Caspase 3, and TUNEL) indicated that: a) An improvement of apoptotic activity was observed for a 28 base pair MORF sequence when compared to MORFs composed of 20 and 25 base pairs. The differences depended on type of assay, concentration and exposure schedule (consecutive vs. premixed). b) The higher the valence of P-(MORF2)x the higher the levels of apoptosis. c) Higher molecular weight of P-(MORF2)x induced higher levels of apoptosis. d) A miniPEG8 spacer was effective in enhancing apoptotic levels in contrast to a miniPEG2 spacer. e) There was not a statistically significant difference when comparing Fab′1F5-MORF1 with Fab′RTX-MORF1.

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Section: Discussionmentioning

confidence: 99%

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

Zhang

Fang

Yang

et al. 2017

Journal of Controlled Release

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“…However, such cocktail treatment usually is limited by the cumulative toxic effects of the free drugs. Polymer-drug conjugates have advantages on maximizing synergy in the therapeutic effects due to long-circulating pharmacokinetics and reduced non-specific toxicity [56]. …”

Section: The Development Of the Second Generation Of Hpma Copolymementioning

confidence: 99%

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

Yang

Kopeček

2017

Current Opinion in Colloid & Interface Science

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It is almost four decades since N-(2-hydroxypropyl)methacrylamide (HPMA) – based copolymers arose as drug carriers. Although fundamentals have been established and significant advantages have been proved, the commercialization of this platform technology was hampered due to modest outcome of clinical trial initiated with PK1, the symbol of first generation polymer-drug conjugates. In this review, we illustrate the exciting progress and approaches offered by more effective 2nd generation HPMA-based polymer-drug conjugates in cancer treatment. For example, a new synthetic strategy endorses inert HPMA polymer with biodegradability, which permitted to prepare high molecular weight HPMA-drug conjugates with simple linear architecture while maintaining good biocompatibility. As expected, extended long-circulating pharmacokinetics and enhanced antitumor activities were achieved in several preclinical investigations. In addition, greater inhibition of tumor growth in combination regimes exhibits the remarkable capability and flexibility of HPMA-based macromolecular therapeutics. The review also discusses the main challenges and strategies for further translation development of 2nd generation HPMA-based polymer-drug conjugates.

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“…Nonetheless, rituximab, similar to most naked mAbs, displays limited clinical effectiveness mainly due to incidence of treatment resistance, relapse, as well as adverse side effects. Importantly, only 40% of the patients who initially respond to rituximab have the ability to respond again after relapse [6,7]. Therefore, there is a need for developing novel therapeutic strategies against rituximab-resistant B-cell lymphoma with improved outcomes.…”

Section: Introductionmentioning

confidence: 99%

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

Abdollahpour‐Alitappeh

Karouei

Lotfinia

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Rituximab is a chimeric monoclonal antibody directed against B-lymphocyte specific antigen CD20, which is used for the treatment of B-cell malignancies. However, the effectiveness of rituximab is limited partly due to treatment resistance. The aim of this study was to develop rituximab-based antibody drug conjugate (ADC) to enhance rituximab activity. In this study, monomethyl auristatin E (MMAE) was covalently conjugated to dithiothreitol -reduced rituximab via a valine-citrulline peptide linker (rituximab-vcMMAE). The conjugates were then characterized by using nonreducing sodium dodecyl sulfate-polyacrylamide electrophoresis (SDS-PAGE) and cell-based enzyme-linked immunosorbent assay (ELISA). The cytotoxic activity of the ADC was evaluated against Raji (human B-cell lymphoma; CD20-positive) and MOLT-4 (T lymphoblast; acute lymphoblastic leukemia; CD20-negative) cell lines. In addition, the colony formation assay was used to identify the propagation ability of ADC-treated cells in vitro. Results from nonreducing SDS-PAGE revealed various species of rituximab-MC-Val-Cit-PABC-MMAE (rituximab-vcMMAE), as compared with unconjugated rituximab. The binding capacity of rituximab-vcMMAE to the CD20-positive cell was similar to that of the parental rituximab. Most importantly, our results revealed that rituximab-vcMMAE was highly potent against the CD20-positive cell line, but not against the CD20-negative cell. At the same time, rituximab-vcMMAE was able to inhibit colony formation in CD20-positive cells. These data indicate that rituximab-vcMMAE may be a highly effective and selective therapy for the treatment of B-cell lymphoma.

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Polymeric biomaterials and nanomedicines

Cited by 17 publications

References 166 publications

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

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