Dual drug loaded vitamin D3 nanoparticle to target drug resistance in cancer

Abstract

Overcoming drug resistance is one of the most challenging problems in cancer chemotherapy. Drug cocktails can overcome the drug resistance. However, multiple drug combinations lead to multifold increment of off-target toxicity, as well as the delivery of the required therapeutic amount of combined drugs remains problematic. To address these problems, we have developed a sub 200 nm vitamin D3 nanoparticle, which can contain a rational combination of dual drugs (PI103 and cisplatin or doxorubicin or proflavine). The size, shape and morphology of these dual drug containing vitamin D3 nanoparticles were characterized by DLS, FESEM, AFM and TEM. The nanoparticles released the dual drugs in high quantity at pH ¼ 5.5 compared to pH ¼ 7.4 in a slow and sustained manner over 72 h with stability over 15 days at 37 C, as well as 4 C. These dual drug loaded nanoparticles induced increased cell death in human hepatocellular carcinoma, Hep3B cells at 24 h compared to monotherapy; moreover, they were effective against cisplatin-resistant cells (Hep3B-R) as well. VitD3-PI103-CDDP-NP and vitD3-PI103-Dox-NP showed cytotoxicity by inducing apoptosis through DNA damage. Furthermore, vitD3-PI103-CDDP-NP showed considerably improved efficacy in 5-fluorouracil (5-FU) resistant Hep3B-5FU-R cells; its activity was even better compared to 5-FU. Finally, vitD3-PI103-proflavine-NP internalized into Hep3B-R cells considerably faster (within 3 minutes) compared to Hep3B cells, as visualized by fluorescent microscopy. Therefore, these dual drug loaded nanoparticles can successfully overcome the trauma of drug resistance and have the potential to be applied into the clinics for improved cancer therapeutics.

Self‐Assembled Oleic Acid Nanoparticle Mediated Inhibition of Mitogen‐Activated Protein Kinase Signaling in Combination with DNA Damage in Cancer Cells

“…Furthermore, MALDI‐TOF experiments demonstrated the characteristic molecular ion peaks for free AZD6244 and cisplatin (Figure S15, S16 in the Supporting Information) to confirm their presence in active form after release from OA‐NPs in pH 5.5 at 24 h. From this drug release experiment, it was clear that OA‐NPs released the dual drugs in much higher quantity at pH 5.5 compared to pH 7.4 in a slow and sustained manner over 4 days. Previously, we have demonstrated that ester bonds between drug–lipid conjugates are more labile in acidic pH compared to physiological pH . Similarly, we anticipate that the ester linkage in oleic‐acid–AZD6244 conjugate ( 2 ) and Pt−O−CO− linkage in oleic‐acid–cisplatin conjugate ( 4 ) are more labile in acidic environment compared to neutral pH.…”

“…Cell viability : Cell viability assay of OA‐NPs using MTT reagents in HeLa, Hep3B, Hep3B‐R and MDA‐MB‐231 cells was performed by following the methods described in references and .…”

“…Previously,w eh ave demonstrated that ester bonds between drug-lipid conjugates are more labile in acidic pH compared to physiological pH. [49,50] Similarly,w ea nticipate that the ester linkage in oleic-acid-AZD6244c onjugate (2)a nd PtÀOÀCOÀ linkagei no leic-acid-cisplatin conjugate (4) are more labile in acidic environmentc ompared to neutral pH. We reasoned that althoughm ost of the free drugsw ere released from the OA-NPs in pH 5.5 at 37 8Ct he drug release would be negligible at storage temperature (4 8C) for 60 days.…”

“…Cell viability: Cell viability assay of OA-NPs using MTT reagents in HeLa, Hep3B, Hep3B-R and MDA-MB-231 cells was performed by following the methods described in references [49] and [50]. Cellular internalization: Confocal laser scanning microscopy (CLSM) to evaluate the cellular internalization of rhodamine encapsulated OA-Rho-NPs in at ime-dependent manner was performed using the methods described in reference [49].…”

Chimeric Nanoparticle: A Platform for Simultaneous Targeting of Phosphatidylinositol-3-Kinase Signaling and Damaging DNA in Cancer Cells

“…[18][19][20][21] Nanocarriers having size < 300 nm can accumulate specifically into the 4 tumor due to unique permeable tortuous angiogenic blood vessels. [22][23][24] Several nanocarriers including liposome, 25,26 polymeric nanoparticles, [27][28][29] dendrimers, 30,31 graphene oxide, 32,33 carbon-nanotubes, 34 mesoporous silica nanospheres, 35 nanocell, 36 gel-liposome, 37 layer-bylayer nanoparticle 38 and minicell 39 have been developed to co-deliver multiple drugs with combination with siRNA, DNA and therapeutic proteins. Despite having huge contribution of nanoplatforms in dual drug delivery in cancer therapeutics, not much attempts have been explored in delivering PI3K signaling inhibitors specifically into tumor to reduce their offtarget effects in healthy tissues as well as overcoming PI3K inhibitor related resistance.…”