Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid‐Based Combination‐Drug Conjugate

Abstract

Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer–drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer–drug conjugates at supramolecular level to allow the design of more effective polymer–drug conjugates.

Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

“…Therefore, high CAA content of MDA‐MB‐231‐Luc tumors may serve as a faithful model to study this phenomenon and develop treatments to avoid adipocytic protumorigenic effects. Furthermore, high‐lipid content and low‐cellular density in the tumor stroma generated a softer tumor mass with a threefold higher EPR effect, thereby providing a model to assess EPR‐related passive tumor accumulation, especially important for the effectiveness of nanomedicinal approaches to cancer treatment . The flexibility and permeability of the MDA‐MB‐231‐Luc model stroma may also provide a means to assess intratumoral administration strategies …”

“…Furthermore, high-lipid content and low-cellular density in the tumor stroma generated a softer tumor mass with a threefold higher EPR effect, thereby providing a model to assess EPR-related passive tumor accumulation, especially important for the effectiveness of nanomedicinal approaches to cancer treatment. 7,30,31 The flexibility and permeability of the MDA-MB-231-Luc model stroma may also provide a means to assess intratumoral administration strategies. 32 The metabolomic comparison of 4T1 and MDA-MB-231-Luc primary tumors suggests that specific metabolic alterations could explain the differences observed in growth rates, with guanosine and uracil (a pyrimidine derivative) the two most relevant soluble metabolites contributing to model discrimination.…”

Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models

“…[11,12] In addition, it has been observed that nanoparticle properties such as chemistry, size, shape, and aspect ratio all have an effect on pharmacokinetics, tumor penetration and organ accumulation. [13][14][15][16][17] These concepts have been reviewed in recent years due to the importance of achieving the appropriate trade-off between nanoparticle characteristics to achieve both prolonged circulation and good penetration into a solid tumor mass. [18][19][20] However, while there have been investigations of many nanoparticle sizes and shapes, there remain questions relating to how nanoparticles of specific sizes and architectures, but retaining the same surface chemistry behave in in vivo environments.…”

A multifunctional biodegradable brush polymer-drug conjugate for paclitaxel/gemcitabine co-delivery and tumor imaging

“…14 Recent studies have also revealed the promising application potential of polymer-drug conjugates (PDCs) as combination nanomedicines. [15][16][17][18][19][20][21][22] Compared with separate administration of PTX and GEM, integrated single nanomedicine formulations for co-delivery of PTX and GEM can simplify the cancer treatment process. 23 However, there is a vast difference in hydrophobicity between PTX and GEM.…”