Article

Polymer-drug conjugates: Progress in polymeric prodrugs

Progress in Polymer Science - PROG POLYM SCI 01/2006; 31(4). DOI: 10.1016/j.progpolymsci.2005.09.004

ABSTRACT Polymers are used as carriers for the delivery of drugs, proteins, targeting moieties, and imaging agents. Several polymers, poly(ethylene glycol) (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), and poly(lactide-co-glycolide) (PLGA) copolymers have been successfully utilized in clinical research. Recently, interest in polymer conjugation with biologically active components has increased remarkably as such conjugates are preferably accumulated in solid tumors and can reduce systemic toxicity. Based on the site and the mode of action, polymer conjugates possess either 'tuned' degradable or non-degradable bonds. In order to obtain such bonds, most of the strategies involve incorporation of amino acids, peptides or small chains as spacer molecules through multiple steps to include protections and deprotections. There is a need to design efficient synthetic methods to obtain polymeric conjugates with drugs and other bioactive components. Designs should aim to decrease the steric hindrance exhibited by polymers and the biocomponents. In addition, the reactivity of polymer and drug must be enhanced. This is especially true for the use of high molecular weight linear polymers and bulkier unstable drugs such as steroids and chemotherapeutic agents. Further, it is essential to elucidate the structure activity relationship (SAR) of a drug when it is conjugated with a polymer using different conjugation sites, as this can vary the efficacy and mechanism of action when compared with its free form. This review will discuss the current synthetic advances in polymer-conjugation with different bioactive components of clinical importance. In addition, the review will describe the strategies for reduction of steric hindrance and increase in reactivity of the polymers, drugs and bioactive agents and highlight the requisite structure activity relationship in polymer–drug bioconjugates. Finally, we will focus on passive and active targeting of polymeric drug delivery systems to specific site of drug action.

0 Bookmarks
 · 
228 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the second most common cause of cancer-related deaths in women. Chemotherapy is an important treatment modality, and paclitaxel (PTX) is often the first-line therapy for its metastatic form. The two most notable limitations related to PTX-based treatment are the poor hydrophilicity of the drug and the systemic toxicity due to the drug's nonspecific and indiscriminate distribution among the tissues. The present work describes an approach to counter both challenges by designing a conjugate of PTX with a hydrophilic macromolecule that is coupled through a biocleavable linker, thereby allowing for active targeting to an enzyme significantly upregulated in cancer cells. The resultant strategy would allow for the release of the active ingredient preferentially at the site of action in related cancer cells and spare normal tissue. Thus, PTX was conjugated to the hydrophilic poly(amdioamine) [PAMAM] dendrimer through the cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly. The PTX prodrug conjugate (PGD) was compared to unbound PTX through in vitro evaluations against breast cancer cells and normal kidney cells as well as through in vivo evaluations using xenograft mice models. As compared to PTX, PGD demonstrated a higher cytotoxicity specific to cell lines with moderate-to-high cathepsin B activity; cells with comparatively lower cathepsin B activity demonstrated an inverse of this relationship. Regression analysis between the magnitude of PGD-induced cytotoxic increase over PTX and cathepsin B expression showed a strong, statistically significant correlation (r(2) = 0.652, p < 0.05). The PGD conjugate also demonstrated a markedly higher tumor reduction as compared to PTX treatment alone in MDA-MB-231 tumor xenograft models, with PGD-treated tumor volumes being 48% and 34% smaller than PTX-treated volumes at weeks 2 and 3 after treatment initiation.
    Molecular Pharmaceutics 05/2014; · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The clinical application of gambogic acid, a natural component with promising antitumor activity, is limited due to its extremely poor aqueous solubility, short half-life in blood, and severe systemic toxicity. To solve these problems, an amphiphilic polymer-drug conjugate was prepared by attachment of low molecular weight (ie, 2 kDa) methoxy poly(ethylene glycol) methyl ether (mPEG) to gambogic acid (GA-mPEG2000) through an ester linkage and characterized by (1)H nuclear magnetic resonance. The GA-mPEG2000 conjugates self-assembled to form nanosized micelles, with mean diameters of less than 50 nm, and a very narrow particle size distribution. The properties of the GA-mPEG2000 micelles, including morphology, stability, molecular modeling, and drug release profile, were evaluated. MTT (3-(4,5-dimethylthiazo l-2-yl)-2,5 diphenyl tetrazolium bromide) tests demonstrated that the GA-mPEG2000 micelle formulation had obvious cytotoxicity to tumor cells and human umbilical vein endothelial cells. Further, GA-mPEG2000 micelles were effective in inhibiting tumor growth and prolonged survival in subcutaneous B16-F10 and C26 tumor models. Our findings suggest that GA-mPEG2000 micelles may have promising applications in tumor therapy.
    International Journal of Nanomedicine 01/2014; 9:243-255. · 4.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present work reported the construction of a drug delivery nanovehicle via pH-sensitive assembly strategy for the improved cellular internalization and intracellular drug liberation. Through spontaneous formation of boronate linkage in the physiological condition, phenylboronic acid modified cholesterol was able to attach onto catechol-pending methoxy poly(ethylene glycol)-block-poly(L-lysine). This comb-type polymer could self-organize into micellar nanoconstruction that is able to effectively encapsulate poorly water-soluble agents. The blank micelles exhibited negligible in vitro cytotoxicity, yet the DOX-loaded micelles could effectively induce cell death at a level comparable to free DOX. Owing to the acidity-labile feature of boronate linkage, environmental pH decline from pH 7.4 to 5.0 could trigger the nanoconstruction dissociation and in turn accelerate the liberation of entrapped drugs. Importantly, the blockage of endosomal acidification in HeLa cells by NH4Cl treatment significantly decreased the nuclear uptake efficiency and cell-killing effect mediated by DOX-loaded nanoassembly, suggesting that acidity-triggered destruction of nanoconstruction is of significant importance to the enhanced drug efficacy. Moreover, confocal fluorescence microscopy and flow cytometry assay revealed the effective internalization of the nanoassemblies, and their cellular uptake efficiency exhibited a cholesterol dose-dependent profile, indicating the contribution of introduced cholesterol functionality to the transmembrane process of the nanoassembly.
    Acta biomaterialia. 05/2014;

Full-text

View
10 Downloads
Available from