New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

Abstract

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound 1 retained high antiproliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile. Cancer Res; 77(24); 6963-74. Ó2017 AACR.

The toxicity of ZnO nanomaterials to HepG2 cells: the influence of size and shape of particles

“…To reduce the toxicity associated with ZnO NM exposure, it may be necessary to use surface coating to change the interactions between ZnO NMs and cells (Cao et al, ; Liu et al, ), or use NMs based on biocompatible materials other than ZnO for biomedical purposes (An & Zhang, ; Wang et al, ). Alternatively, targeted drug delivery to realize accumulation of toxic ZnO NMs at specific sites could also be considered (Cai et al, ; Feng, Ding, Gref, & Shen, ; Shi et al, ; Wang et al, ).…”

Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

“…The sss‐CTX approach, while reducing the surfactant‐content, did not reduce the toxicity of the formulation in these conditions, which is a desirable goal with new taxane formulations. Alternative approaches, such as chemically‐modified prodrug carrier formulations may be promising in this regard …”

Photodynamic Therapy, a Potential Therapy for Improve Cancer Management

“…The use of nanoparticles makes it able to explore the poor lymphatic drainage and ensure that the photosensitizers is much more easily retained in cancer-like tissues than in normal tissues, a phenomena known as enhanced permeability and retention effect [79]. The conjugation of anticancer photosensitizers and water-dispersible nanoparticles with specific affinity for cancer stem cells yields a systemic self-deliverable photodynamic therapy, which maintains the pharmacological efficacy while improving the safety and delivery profiles [78,80]. The nanocarriers are known to achieve both passive and active targeting delivery, which is an additional benefit to increase the therapeutic effects and reduce the side-effects [81].…”