Calcium phosphate-polymer hybrid nanoparticles for enhanced triple negative breast cancer treatment via co-delivery of paclitaxel and miR-221/222 inhibitors

Abstract

In this study, a development of a novel calcium phosphate-polymer hybrid nanoparticle system is reported.The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties (i.e., inhibitors for microRNA-221 and microRNA-222 (miRi-221/222) and paclitaxel (pac)).miRi-221/222 are hydrophilic and were encapsulated with calcium phosphate by co-precipitation in a water-in-oil emulsion.The precipitates were then coated with an anionic lipid, dioleoylphosphatidic acid (DOPA), to co-encapsulate hydrophobic paclitaxel outside the hydrophilic precipitates and inside the same nanoparticle.The nanoparticles formed by following this approach had a size of about ≤100nm and contained both lipid-coated calcium phosphate/miRi and paclitaxel.This nanoparticle system was found to simultaneously deliver paclitaxel and miRi-221/222 to their intracellular targets, leading to inhibit proliferative mechanisms of miR-221/222 and thus significantly enhancing the therapeutic efficacy of paclitaxel.

Delayed Sequential Co-Delivery of Gefitinib and Doxorubicin for Targeted Combination Chemotherapy

“…25–28 A di-block copolymer, PLA- b -mPEG, was made by conjugating PLA-COOH (15 kDa) with H 2 N-mPEG (5 kDa) through the carbodiimide-mediated coupling reaction. 28–30 Dox-conjugated PLA- b -mPEG (Dox-PLA-PEG) was prepared by following published procedures. 31–34 Unreacted Dox was removed by dialyzing Dox-PLA-PEG against water for 24 hrs (MWCO 3.5 kDa).…”

Progress in nonviral gene therapy for breast cancer and what comes next?

“…However, their clinical application requires biocompatibility and the absence of antigenic activation, which is usually achieved by creating hybrid nanosystems with surfactants coating or lipid modifications. Genes can be loaded onto positively charged coatings, encapsulated into calcium phosphate nanoparticles by means of electrostatic interactions, or conjugated to cleavable linkers onto the nanoparticle surface [31][32][33].…”

“…Gold nanoparticles and nanorods are instead investigated for photothermal gene delivery, in which electrostatically bound DNA can be released from the complex under laser radiation without disruption of the genetic material [32,35]. In recent years, calcium phosphate nanoparticles have been intensively reconsidered in DNA/RNA delivery for breast cancer therapy [31,33]. As other cations, they can form stable ionic complexes with a considerable payload of nucleic acids, and possess high transfection capability and easy biodegradation.…”

“…As other cations, they can form stable ionic complexes with a considerable payload of nucleic acids, and possess high transfection capability and easy biodegradation. Major concerns that limited the use of these nanoparticles have been overcome by the coupling with polymeric systems, PEG or lipid shells, reducing aggregation and increasing nanoparticle stealth and cellular penetration [31][32][33]. Different strategies for inorganic nanoparticles functionalization with aptamers or other targeting ligands have greatly improved the selective targeting of breast cancer cells and transfection efficiency [17].…”

“…Therefore, both miRNA mimics and miRNA inhibitors have been developed and successfully tested as therapeutic agents to achieve breast tumor regression. In particular, miRNA-based therapeutic strategies are now extensively explored in breast cancer preclinical models in order to regulate the expression of oncogenic genes and pathways and the interaction with the immune microenvironment, to modify the expression of surface markers, and to restore cancer cells sensitivity to therapy [33,36,42,44,62,71,74,78]. This is particularly relevant for aggressive cancers that still lack effective drugs, such as TNBC, or in case of onset of resistance.…”