Delivery strategies for macromolecular drugs in cancer therapy

With the development of biotherapy,biomacromolecular drugs have gained tremendous attention recently,especially in drug development field due to the sophisticated functions in vivo.Over the past few years,a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability,e.g.,the instability and easily restricted by physiologic barriers.The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life,increase the bioavailability,or improve patient compliance,which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs.In this review,recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized,mainly drawing on the development over the last five years.

Poly(ethylene oxide)-graft-methotrexate Macromolecular Drugs Conjugating via Aminopteridine Ring Exhibit Potent Anticancer Activity

Water soluble poly(ethylene oxide)-graft-methotrexate (PEO-g-MTX) conjugates with a robust amide linkage via the amine or carboxylic acid groups of MTX were designed,prepared and investigated for in vitro anti-tumor effects.MTX was conjugated to multi-functional PEO containing multiple pendant carboxylic acid (PEO-g-COOH)or amine groups (PEO-g-NH2) via the carbodiimide chemistry,which afforded PEO-g-MTX conjugates with an amide bond to the aminopteridine ring or carboxylic acid groups of MTX (denoted as PEO-g-MTX(COOH) and PEO-g-MTX(NH2),respectively).Dynamic light scattering (DLS) revealed that all PEO-g-MTX conjugates,with MTX contents varying from 4.8 to 19.6 wt％,existed as unimers in phosphate buffer (PB,pH 7.4,20 mmol·L-1).Interestingly,MTT assays showed that PEO-g-MTX(COOH) exhibited potent anti-tumor activity in HeLa,A549,KB and NIH3T3 cells with cytotoxicity profiles comparable to that of free MTX.In contrast,PEO-g-MTX(NH2)revealed diminishing cytostatic effect with IC50 (half maximal inhibitory concentration) ten to hundred times higher than that of PEO-g-MTX(COOH).Moreover,PEO-g-MTX(COOH) conjugates allowed facile conjugation with targeting ligands.Notably,folate-decorated PEO-g-MTX(COOH) macromolecular drugs showed apparent targetability to folate receptor-overexpressing KB cells with an IC50 over 12-fold lower than non-targeting PEO-g-MTX-(COOH) control and about 2-fold lower than free MTX under otherwise the same conditions.

Enhanced permeability and retention effect based nanomedicine, a solution for cancer

Tumor-targeting is becoming more and more important for cancer chemotherapy. Though many molecular-target drugs have been developed in the past two decades which shed some light on targeted tumor therapy,clinical results of those molecular-target drugs are not so encouraging especially for solid tumors, problems mostly relating to the heterogeneity and mutations of target molecules in human solid tumors. More general tumor-targeting strategy is thus anticipated. In this regard, the enhanced permeability and retention(EPR) effect which is a unique phenomenon of solid tumors based on the anatomical and pathophysiological nature of tumor blood vessels, is receiving more and more attentions. This EPR effect now served as a standard for tumor-targeted macromolecular anticancer therapy, namely nanomedicine. Many nanoplatforms have been developed as targeted drug delivery systems, including liposome, polymeric micelles, polymer conjugate, nanoparticles. Ample macromolecular drugs are now approved for clinical use or in clinical stage development, all of which by taking advantage of EPR effect, show superior in vivo pharmacokinetics and remarkable tumor selectivity, resulting in improved antitumor effects with less adverse effects. We thus believe EPR-based nanomedicine will be a solution for cancer in the future, whereas further consideration of factors involved in EPR effect and strategies to augment/improve EPR effect are warranted.

Developing macromolecular therapeutics:the future drug-of-choice

Macromolecular drugs including peptides,proteins,antibodies,polysaccharides and nucleic acids have been widely used for therapy of major diseases such as carcinoma and AIDS as well as cardiovascular and neurodegenerative disorders among other medical conditions.Due to their unmatched properties of high selectivity and efficiency,macromolecular drugs have been recognized as the drug-of-choice of the future.Since worldwide progress on macromolecular therapeutics still remains in the infant stage and is therefore wide open for equalground competition,R&D related to macromolecular drugs should be considered as the main point of focus in China in setting up its strategic plans in pharmaceutical development.In this article,research strategies and drug delivery approaches that should be adopted to enhance the therapeutic effects of macromolecular drugs are reviewed.In addition,comments concerning how to implement such strategies to excel from competition in this challenging research field,such as the design of innovative and highly effective delivery systems of macromolecular drugs with self-owned intellectual property rights,are provided.