Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models

Abstract

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

The Application of Biomaterials in the Treatment of Platinum‐Resistant Ovarian Cancer

“…Poly(lactic-co-glycolic acid) (PLGA) and poly(ethyleneg lycol) (PEG) are biomaterials that are often used for drug delivery due to their biocompatibility.Z hang et al successfully encapsulatedwortmannin (Wtmn) and amodified version of cisplatin into FDA-approved nanoparticles fabricated with PLGA-PEG. [86] They were able to successfully encapsulate the hydrophilic drug, cisplatin,i nto NPs with ah ydrophobic core by using caprylic acid modified Pt IV cisplatin prodrug (CPP) which enhanced cisplatin's hydrophobicity.Z hang et al reported that the PLGA-PEG NPss uccessfully improved the cytotoxicity (22-fold) on A2780cis cells (i.e.,c isplatin resistant cells) and displayed strong treatment synergy( CI % 0.04). Free CPP also hada ni nhibitorye ffect on mice xenografted with A2780cis cells, however required higherd oses to obtain the same effect as the co-druge ncapsulation in NPs.…”

“…Furthermore, previous works have reported the accumulationo fP LGA-PEG NPs in the liver and kidneys,h owever Zhang et al reported that treatment with co-encapsulated NPs in mice xenografted with A2780cis showedn oi ncrease in serum liver and kidneyt oxicity markers above normall evels. [86,[91][92][93][94][95] The co-delivery of cisplatin and Wtmn with the PLGA-PEG NPs synergistically enhanced chemoradiotherapy (CRT) and reversedc isplatin resistance. Wtmn is a phosphoinositide 3-kinase (PI3K) inhibitor that can block downstream DNA repair pathways and potently re-sensitize cancer cells.…”

“…Reprinted with permission from Ref. [86],Copyright2 018 Elsevier. 22 and 19 biotin molecules attached, respectively) for the encapsulation of cisplatin to treat OCpt.…”

“…[86] Aggressive ovarian cancer treatment usually involves surgery followed by ap latinum-based chemotherapy,h owever while the cancer is responsivet ot his type of treatment, many patients will relapse within ay ear. [86] The majority of relapse cases occur due to the development of ar esistancet op latinum-based chemotherapy. Metal transport proteins are responsible for the cellular intake of Pt drugs and have been associatedt ob ed ownregulated with platinum ovarian resistant cell lines.…”

“…[84,[121][122][123] The platinum-resistant phenotype responds poorly to second line chemotherapies creating ad emand for new strategies that could be used to target OCpt. As discussed above, one of the strategies is to use biomaterials to deliver the platinum-resistant drugs more efficiently.A sd iscussed in this review,s everal groups have developed biomaterials to deliverc isplatin/cisplatin prodrug [51,55,59,64,71,86] or carboplatin/carboplatin prodrug [58,70] with or withoutsiRNAs.…”