Designing polymer conjugates as lysosomotropic nanomedicines

2007 ◽  
Vol 35 (1) ◽  
pp. 56-60 ◽  
Author(s):  
R. Duncan
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Molecular Mass ◽  
Anticancer Agents ◽  
Synthetic Polymer ◽  
Water Soluble ◽  
Hpma Copolymer ◽  
Polymer Conjugates ◽  
Drug Conjugates ◽  
Polymer Drug Conjugates

Marriage of cell biology (the concept of ‘lysosomotropic drug delivery’) and the realization that water-soluble synthetic polymers might provide an ideal platform for targeted drug delivery led to the first synthetic polymer–drug conjugates that entered clinical trials as anticancer agents. Conceptually, polymer conjugates share many features with other macromolecular drugs, but they have the added advantage of the versatility of synthetic chemistry that allows tailoring of molecular mass and addition of biomimetic features. Conjugate characteristics must be optimized carefully to ensure that the polymeric carrier is biocompatible and that the polymer molecular mass enables tumour-selective targeting followed by endocytic internalization. The polymer–drug linker must be stable in transit, but be degraded at an optimal rate intracellularly to liberate active drug. Our early studies designed two HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer conjugates containing doxorubicin that became the first synthetic polymer–drug conjugates to be tested in phase I/II clinical trials. Since, a further four HPMA copolymer–anticancer drug conjugates (most recently polymer platinates) and the first polymer-based γ-camera imaging agents followed. Polymer–drug linkers cleaved by lysosomal thiol-dependent proteases and the reduced pH of endosomes and lysosomes have been used widely to facilitate drug liberation. It is becoming clear that inappropriate trafficking and/or malfunction of enzymatic activation can lead to new mechanisms of clinical resistance. Recent studies have described HPMA copolymer conjugates carrying a combination of both endocrine and chemotherapy that are markedly more active than individual conjugates carrying a single drug. Moreover, current research is investigating novel dendritic polymer architectures and novel biodegradable polymers as drug carriers that will provide improved drug delivery and imaging probes in the future. The present paper reviews the clinical status of polymeric anticancer agents, the rationale for the design of polymer therapeutics and discusses the benefits and challenges of lysosomotropic delivery.

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S189-S199 ◽  
Author(s):  
R Duncan ◽  
M J Vicent ◽  
F Greco ◽  
R I Nicholson
Keyword(s):  
Clinical Trials ◽  
Anticancer Agents ◽  
Antitumour Activity ◽  
Metastatic Cancer ◽  
Clinical Results ◽  
Water Soluble ◽  
Current Status ◽  
Hpma Copolymer ◽  
Drug Conjugates

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Design, Synthesis and Studies on Novel Polymeric Prodrugs of Erlotinib for Colon Drug Delivery

2020 ◽  
Vol 20 ◽  
Author(s):  
Sahil Kumar ◽  
Bandna Sharma ◽  
Tilak R. Bhardwaj ◽  
Rajesh K. Singh
Keyword(s):  
Drug Delivery ◽  
Colon Cancer ◽  
Drug Release ◽  
Anticancer Agents ◽  
Release Kinetics ◽  
In Vitro Release ◽  
Specific Treatment ◽  
Drug Conjugates ◽  
Polymer Drug Conjugates

Aims: In the present study, polymer-drug conjugates were synthesized based on azo-bond cleavage drug delivery approach for targeting erlotinib as anticancer drug specifically to the colon for the proficient treatment of colon cancer. Background: Colon cancer (CC) is the third commonly detected tumor worldwide and it make up about 10 % of all cases of cancers. Most of the chemotherapeutic drugs available for treating colon cancer are not only toxic to cancerous cells but also to the normal healthy cells. Among the various approaches to get rid of the adverse effects of anticancer agents, prodrugs are one of the most imperative approaches. Objective: The objective of the study is to chemically modify the erlotinib drug through azo-bond linkage and suitable spacer which will be finally linked to polymeric backbone to give desired polymer linked prodrug. The azo reductase enzyme present in colon is supposed to cleave the azo-bond specifically and augment the drug release at the colon. Methods: The synthesized conjugates were characterized by IR and 1H-NMR spectroscopy. The cleavage of aromatic azobond resulted in a potential colon-specific liberation of drug from conjugate studied in rat fecal contents. In vitro release profiles of polyphosphazene-linked conjugates of erlotinib have been studied at pH 1.2, pH 6.8 and pH 7.4. The stability study was designed to exhibit that free drug was released proficiently and unmodified from polyphosphazene-erlotinib conjugates having aromatic azo-bond in artificial colon conditions. Results: The synthesized conjugates were demonstrated to be stable in simulated upper gastro-intestinal tract conditions. The drug release kinetics shows that all the polymer-drug conjugates of erlotinib follow zero-order release kinetics which indicates that the drug release from the polymeric backbone is independent of its concentration. Kinetic study of conjugates with slope (n) shows the anomalous type of release with an exponent (n) > 0.89 indicating a super case II type of release. Conclusion: These studies indicate that polyphosphazene linked drug conjugates of erlotinib could be the promising candidates for the site-specific treatment of colon cancer with least detrimental side-effects.

scholarly journals Polymer-Drug Conjugates in Inflammation Treatment

2018 ◽  
pp. S281-S292 ◽  
Author(s):  
E. KOZIOLOVÁ ◽  
K. VENCLÍKOVÁ ◽  
T. ETRYCH
Keyword(s):  
Multiple Sclerosis ◽  
Lupus Erythematosus ◽  
Defense Mechanism ◽  
Water Soluble ◽  
Active Targeting ◽  
Water Soluble Polymer ◽  
Polymer Backbone ◽  
Polymer Conjugates ◽  
Drug Conjugates ◽  
Polymer Drug Conjugates

Inflammation is a vital defense mechanism of living organisms. However, persistent and chronic inflammation may lead to severe pathological processes and evolve into various chronic inflammatory diseases (CID), e.g. rheumatoid arthritis, multiple sclerosis, multiple sclerosis, systemic lupus erythematosus or inflammatory bowel diseases, or certain types of cancer. Their current treatment usually does not lead to complete remission. The application of nanotherapeutics may significantly improve CID treatment, since their accumulation in inflamed tissues has been described and is referred to as extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS). Among nanotherapeutics, water-soluble polymer-drug conjugates may be highly advantageous in CID treatment due to the possibility of their passive and active targeting to the inflammation site and controlled release of active agents once there. The polymer-drug conjugate consists of a hydrophilic biocompatible polymer backbone along which the drug molecules are covalently attached via a biodegradable linker that enables controlled drug release. Their active targeting or bio-imaging can be achieved by introducing the cell-specific targeting moiety or imaging agents into the polymer conjugate. Here, we review the relationship between polymer conjugates and inflammation, including the benefits of the application of polymer conjugates in inflammation treatment, the anti-inflammatory activity of polymer drug conjugates and potential polymer-promoted inflammation and immunogenicity.

Paclitaxel-albumin interaction in view of molecular engineering of polymer-drug conjugates

2009 ◽  
Vol 81 (3) ◽  
pp. 439-450 ◽  
Author(s):  
Michael Hess ◽  
Byung-Wook Jo ◽  
Stefan Wunderlich
Keyword(s):  
Anticancer Agent ◽  
Molecular Engineering ◽  
Water Soluble ◽  
Hydrophobic Core ◽  
Water Soluble Polymer ◽  
Polymer Conjugates ◽  
Drug Conjugates ◽  
Model Protein ◽  
Polymer Drug Conjugates ◽  
Kinetics Of

The interaction of water-soluble polymer conjugates of the anticancer agent paclitaxel and albumin as model protein has been investigated using fluorescence spectroscopy and NMR. Drugs and drug conjugates can enter the hydrophobic core of albumin; the kinetics of the interaction with the fluorophore, however, differs. Given the information about the steric situation of the formed complexes, some aspects of molecular engineering of the drug are discussed.

scholarly journals Low molecular mass chitosan as carrier for a hydrodynamically balanced system for sustained delivery of ciprofloxacin hydrochloride

2012 ◽  
Vol 62 (2) ◽  
pp. 237-250 ◽  
Author(s):  
Anurag Verma ◽  
Ashok Bansal ◽  
Amitava Ghosh ◽  
Jayanta Pandit
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Molecular Mass ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Water Soluble ◽  
Sustained Delivery ◽  
Ciprofloxacin Hydrochloride ◽  
Water Soluble Drug ◽  
Major Interest

Low molecular mass chitosan as carrier for a hydrodynamically balanced system for sustained delivery of ciprofloxacin hydrochloride Chitosan has become a focus of major interest in recent years due to its excellent biocompatibility, biodegradability and non-toxicity. Although this material has already been extensively investigated in the design of different types of drug delivery systems, it is still little explored for stomach specific drug delivery systems. The objective of the present investigation was to explore the potential of low molecular mass chitosan (LMCH) as carrier for a hydrodynamically balanced system (HBS) for sustained delivery of water soluble drug ciprofloxacin hydrochloride (CP). Various formulations were prepared by physical blending of drug and polymer(s) in varying ratios followed by encapsulation into hard gelatin capsules. All the formulations remained buoyant in 0.1 mol L-1 HCl (pH 1.2) throughout the experiment. Effect of addition of xanthan gum (XG) or ethyl cellulose (EC) on drug release was also investigated. Zero order drug release was obtained from the formulations containing LMCH alone or in combination with XG, and in one instance also with EC. Our results suggest that LMCH alone or in combination with XG is an excellent material for stomach specific sustained delivery of CP from hydrodynamically balanced single unit capsules.

Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin

1999 ◽  
Vol 61 (3) ◽  
pp. 281-294 ◽  
Author(s):  
Richard B Greenwald ◽  
Charles D Conover ◽  
Annapurna Pendri ◽  
Yun H Choe ◽  
Anthony Martinez ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Ethylene Glycol ◽  
Anticancer Agents ◽  
Water Soluble ◽  
Poly Ethylene Glycol ◽  
Poly Ethylene ◽  
Ethylene Glycol Derivatives ◽  
Derivatives Of

Albumin–Polymer–Drug Conjugates: Long Circulating, High Payload Drug Delivery Vehicles

2016 ◽  
Vol 5 (10) ◽  
pp. 1089-1094 ◽  
Author(s):  
Anton A. A. Smith ◽  
Kaja Zuwala ◽  
Oliver Pilgram ◽  
Karen Singers Johansen ◽  
Martin Tolstrup ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Vehicles ◽  
Drug Conjugates ◽  
Delivery Vehicles ◽  
Polymer Drug Conjugates ◽  
High Payload
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