Poly(Malic Acid) Nanoconjugates Containing Various Antibodies and Oligonucleotides for Multitargeting Drug Delivery

Abstract

Nanoconjugates are emerging as promising drug-delivery vehicles because of their multimodular structure enabling them to actively target discrete cells, pass through biological barriers and simultaneously carry multiple drugs of various chemical nature. Nanoconjugates have matured from simple devices to multifunctional, biodegradable, nontoxic and nonimmunogenic constructs, capable of delivering synergistically functioning drugs in vivo. This review mainly concerns the Polycefin family of natural-derived polymeric drug-delivery devices as an example. This type of vehicle is built by hierarchic conjugation of functional groups onto the backbone of poly(malic acid), an aliphatic polyester obtained from the microorganism Physarum polycephalum. Particular Polycefin variants target human brain and breast tumors implanted into animals specifically and actively and could be detected easily by noninvasive imaging analysis. Delivery of antisense oligonucleotides to a tumor-specific angiogenic marker using Polycefin resulted in significant inhibition of tumor angiogenesis and increase of animal survival. Keywordsbiodegradable; brain cancer; breast cancer; imaging analysis; multiple antibodies; multiple drug delivery; multitargeting; Polycefin; poly(malic acid); tumor angiogenesis Engineering of polymeric biodegradable nanoconjugates represents one of the rapidly emerging and important areas of nanotechnology and nanomedicine. In the context of this review, these nanoconjugates will be discussed mostly in relation to anticancer drug delivery. Polymeric nanoconjugates are characterized by multiple covalently attached NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript functional moieties that can target cellular and molecular markers of diseased tissues specifically to achieve maximum treatment efficacy. An outstanding feature of polymeric nanoconjugates is that they can carry a variety of covalently bound drugs that may act simultaneously on several targets (e.g., mRNA and/or protein). The benefit of such drug carriers is that they deliver more than one prodrug by single conjugate molecule, increasing the probability of coordinate and synergistic action and thus providing an efficient inhibition of multiple aberrant tumor pathways. Owing to the specific targeting of tumor tissue/cells, nanoconjugates provide therapeutically efficacious drug concentrations at the site of treatment and minimal side effects on healthy tissue. Nanoconjugate delivery systems are significantly different from nonconjugated nanodelivery vehicles, for example, micelles and liposomes, which also combine drugs, targeting and/or other functional moieties but do not form a covalently linked chemical entity.Devices lacking this entity are prone to continuously lose their constituents by spontaneous or damage-induced leakage and this could be a source of toxicity to healthy tissue or disparities in initially balanced drug compositions.Biodegradability and lack of immunogenicity are other criteria important for treatment tha...

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