Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Abstract

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconju-gate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…Thus, nanodrugs designed to knockdown both wild-type and mutated genes are necessary to overcome these compensatory mechanisms. Antisense oligonucleotides attached to polymalic acid biopolymer that block wild-type EGFR and mutated EGFRvIII receptor synthesis have been successfully used to treat triple negative breast cancer [60] employing a strategy based on acquired mutations by the MDA-MB-468 breast cancer cell line.…”

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

“…The described example reflects our experience with other polymalic acid-based nano drugs indicating a high degree of predictability, reproducibility and absence of notable toxicity. Recent results on toxicity and efficacy of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment are in strong support of this notion 18 . A key feature is that our nano drug is able to penetrate bio-barriers: the endothelial barrier by extravasation into the tumor interstitial, the tumor cell membrane by endosome uptake, and endosome membrane disruption by action of the leucine ethylester or trileucine groups.…”

“…In the example, Herceptin binding to HER2 and specific antisense oligonucleotide annealing with HER2-coding mRNA resulted in sustained blocking of HER2-signaling and severe reduction of HER2-positive breast cancer. Based on the underlying principle of tumor targeting and inhibition of gene expression by antisense oligonucleotides we have to-date synthesized several other nano drugs and successfully inhibited preclinical human glioblastoma and triple-negative breast cancer 11,14–18 .…”

New promising biodegradable polyesters derived from poly((R,S)-3,3-dimethylmalic acid) for cardiovascular applications

“…These biodegradable polyesters were used either alone or as copolymers side chains to improve their mechanical properties, hydrolysis, long-term biodegradation, or biocompatibility behavior for the desired therapeutic applications (PLGA [9,10], PLMA [11][12][13][14][15], etc.). Among this class of polymers, the PMLA is known to present good biocompatibility, non-toxicity in vitro and in vivo, non--immunogenic properties, and stability in the bloodstream [5,[16][17][18][19]. The particularity of this family of polyesters is the presence of functionalized groups in their side chain which, furthermore, allow chemical modification for grafting, thus delivering drugs [20].…”

“…Biopolyesters are widely recommended in biomedical applications [1] as drug carriers [2] such as poly(L-lactic acid) (PLA), poly(glycolic acid) (PGA), poly(ε--caprolactone) (PCL) [3], and poly(malic acid) (PMLA) [4][5][6][7][8]. These biodegradable polyesters were used either alone or as copolymers side chains to improve their mechanical properties, hydrolysis, long-term biodegradation, or biocompatibility behavior for the desired therapeutic applications (PLGA [9,10], PLMA [11][12][13][14][15], etc.).…”