Hemda Baabur-Cohen

Administration, distribution, metabolism and elimination of polymer therapeutics.

Polymer conjugation is an efficient approach to improve the delivery of drugs and biological agents, both by protecting the body from the drug (by improving biodistribution and reducing toxicity) and by protecting the drug from the body (by preventing degradation and enhancing cellular uptake). This review discusses the journey that polymer therapeutics make through the body, following the ADME (absorption, distribution, metabolism, excretion) concept. The biological factors and delivery system parameters that influence each stage of the process will be described, with examples illustrating the different solutions to the challenges of drug delivery systems in vivo.

Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of individually-conjugated drugs

Paclitaxel and doxorubicin are potent anticancer drugs used in the clinic as mono-therapies or in combination with other modalities to treat various neoplasms. However, both drugs suffer from side effects and poor pharmacokinetics. These two drugs have dissimilar physico-chemical properties, pharmacokinetics and distinct mechanisms of action, toxicity and drug resistance. In order to target both drugs selectively to the tumor site, we conjugated them at a synergistic ratio to a biocompatible and biodegradable polyglutamic acid (PGA) backbone. Drugs conjugation to a nano-sized polymer enabled preferred tumor accumulation by passive targeting, making use of the enhanced permeability and retention (EPR) effect. The rational design presented here resulted in co-delivery of combination of the drugs and their simultaneous release at the tumor site. PGA-paclitaxel-doxorubicin nano-sized conjugate exhibited superior anti-tumor efficacy and safety compared to the combination of the free drugs or a mixture of the drugs conjugated to separate polymer chains, at equivalent concentrations. This novel polymer-based multi-drug nano-sized conjugate allowed for true combination therapy since it delivered both drugs to the same target site at the ratio required for synergism. Using mice bearing orthotopic mammary adenocarcinoma, we demonstrate here the advantage of a combined polymer therapeutic bearing two synergistic drugs on the same polymer backbone, compared to each drug bound separately to the backbone.

Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release

Polymeric nanocarriers conjugated with low molecular weight drugs are designed in order to improve their efficacy and toxicity profile. This approach is particularly beneficial for anticancer drugs, where the polymer-drug conjugates selectively accumulate at the tumor site, due to the enhanced permeability and retention (EPR) effect. The conjugated drug is typically inactive, and upon its pH- or enzymatically-triggered release from the carrier, it regains its therapeutic activity. These settings lack information regarding drug-release time, kinetics and location. Thereby, real-time non-invasive intravital monitoring of drug release is required for theranostics (therapy and diagnostics). We present here the design, synthesis and characterization of a theranostic nanomedicine, based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, owing its fluorescence-based monitoring of site-specific drug release to a self-quenched near-infrared fluorescence (NIRF) probe. We designed two HPMA copolymer-based systems that complement to a theranostic nanomedicine. The diagnostic system consists of self-quenched Cy5 (SQ-Cy5) as a reporter probe and the therapeutic system is based on the anticancer agent paclitaxel (PTX). HPMA copolymer-PTX/SQ-Cy5 systems enable site-specific release upon enzymatic degradation in cathepsin B-overexpressing breast cancer cells. The release of the drug occurs concomitantly with the activation of the fluorophore to its Turn-ON state. HPMA copolymer-SQ-Cy5 exhibits preferable body distribution and drug release compared with the free drug and probe when administered to cathepsin B-overexpressing 4T1 murine mammary adenocarcinoma-bearing mice. This approach of co-delivery of two complementary systems serves as a proof-of-concept for real-time deep tissue intravital orthotopic monitoring and may have the potential use in clinical utility as a theranostic nanomedicine.

In vivo comparative study of distinct polymeric architectures bearing a combination of paclitaxel and doxorubicin at a synergistic ratio

ABSTRACT Nowadays, combination therapy became a standard in oncology. In this study, we compare the activity of two polymeric carriers bearing a combination of the anticancer drugs paclitaxel (PTX) and doxorubicin (DOX), which differ mainly in their architecture and supramolecular assembly. Drugs were covalently bound to a linear polymer, polyglutamic acid (PGA) or to a dendritic scaffold, polyglycerol (PG) decorated with poly(ethylene glycol) (PEG), forming PGA‐PTX‐DOX and PG‐PTX‐bz‐DOX‐PEG, respectively. We explored the relationship between the polymeric architectures and their performance with the aim to augment the pharmacological benefits of releasing both drugs simultaneously at the tumor site at a synergistic ratio. We recently designed and characterized a PGA‐PTX‐DOX conjugate. Here, we describe the synthesis and characterization of PG dendritic scaffold bearing the combination of PTX and DOX. The performance of both conjugates was evaluated in a murine model of mammary adenocarcinoma in immunocompetent mice, to investigate whether the activity of the treatments is affected by the immune system. Drug conjugation to a nano‐sized polymer enabled preferred tumor accumulation by extravasation‐dependent targeting, making use of the enhanced permeability and retention (EPR) effect. Both PGA‐PTX‐DOX and PG‐PTX‐bz‐DOX‐PEG nano‐sized conjugates exhibited superior anti‐tumor efficacy and safety compared to the combination of the free drugs, at equivalent concentrations. However, while PGA‐PTX‐DOX was more efficient than a mixture of each drug conjugated to a separate PGA chain, as was previously shown, PG‐PTX‐bz‐DOX‐PEG had similar activity to the mixture of the PG‐PTX‐bz‐PEG and PG‐DOX‐PEG conjugates. Our results show that both conjugates are potential candidates as precision combination nanomedicines for the treatment of breast cancer.

Targeting NCAM-expressing neuroblastoma with polymeric precision nanomedicine

&NA; Neural cell adhesion molecule (NCAM) expression is known to be associated with an aggressive biological behavior, increased metastatic capacity and expression of stem‐cell markers in several tumor types. NCAM was also found to be expressed on tumor endothelial cells while forming new capillary‐like tubes, but not on normal endothelial cells. An NCAM‐targeted polymer‐drug conjugate can be used both to target tumors expressing high levels of NCAM as well as the angiogenic vessels and cancer stem cells populations characterized by NCAM expression within tumors. Here, we describe the design, synthesis, physico‐chemical characterization and the biological evaluation of an NCAM‐targeted conjugate of polyglutamic acid with paclitaxel that was developed and evaluated on neuroblastoma, a high NCAM‐expressing tumor. This conjugate inhibited tumor growth to a higher extent compared to the control conjugates and was less toxic than free paclitaxel. The dose of the conjugate could be increased at least twice than the maximum tolerated dose of paclitaxel to achieve better activity without aggravating toxicity. This work presents evidence that NCAM targeting can highly increase the efficacy of nanomedicines in the appropriate tumor models. Graphical abstract Figure. No caption available.

Integrin-targeted nano-sized polymeric systems for paclitaxel conjugation: a comparative study

Abstract The generation of rationally designed polymer therapeutics via the conjugation of low molecular weight anti-cancer drugs to water-soluble polymeric nanocarriers aims to improve the therapeutic index. Here, we focus on applying polymer therapeutics to target two cell compartments simultaneously – tumour cells and angiogenic endothelial cells. Comparing different polymeric backbones carrying the same therapeutic agent and targeting moiety may shed light on any correlation between the choice of polymer and the anti-cancer activity of the conjugate. Here, we compared three paclitaxel (PTX)-bound conjugates with poly-l-glutamic acid (PGA, 4.9 mol%), 2-hydroxypropylmethacrylamide (HPMA, 1.2 mol%) copolymer, or polyethyleneglycol (PEG, 1:1 conjugate). PGA and HPMA copolymers are multivalent polymers that allow the conjugation of multiple compounds within the same polymer backbone, while PEG is a bivalent commercially available Food and Drug Administration (FDA)-approved polymer. We further conjugated PGA–PTX and PEG–PTX with the integrin αvβ3-targeting moiety RGD (5.5 mol% and 1:1 conjugate, respectively). We based our selection on the overexpression of integrin αvβ3 on angiogenic endothelial cells and several types of cancer cells. Our findings suggest that the polymer structure has major effect on the conjugates activity on different tumour compartments. A multivalent PGA–PTX–E-[c(RGDfK)2] conjugate displayed a stronger inhibitory effect on the endothelial compartment, showing a 50% inhibition of the migration of human umbilical vein endothelial cell cells, while a PTX–PEG–E-[c(RGDfK)2] conjugate possessed enhanced anti-cancer activity on MDA-MB-231 tumour cells (IC50 = 20 nM versus IC50 300 nM for the PGA conjugate).

Liposomes and Polymers in Folate-Targeted Cancer Therapeutics

In this chapter, we will address the therapeutic potential of targeting liposomes and polymers to the folate receptor for delivery of anticancer drugs and review the experimental data in this field. By exploiting the pharmacologic attributes of liposomes and polymers together with their cellular internalization by folate receptor-mediated endocytosis, these systems should allow for improved selectivity and control of drug delivery to folate receptor expressing cancers. Particularly, extension of circulation time and enhanced deposition in tumors coupled with reduced toxicity of liposome- and polymer-associated drugs are important assets of the nanomedicine platform when compared to free drugs or low-molecular weight conjugates. In addition, the high drug:ligand ratio of liposomes and some polymers enable the delivery of a high drug payload per ligand–receptor interaction. However these systems have also some in vivo limitations that will be discussed. It remains unclear whether folate-targeted nanomedicines can provide a significant added value in clinical applications vis-a-vis folate-targeted drug conjugates.