Tunable Hydrophile–Lipophile Balance for Manipulating Structural Stability and Tumor Retention of Amphiphilic Nanoparticles

Abstract

reported that the optimized size may also improve the delivery efficiency in tumors [4] and NPs with moderate rigidity could enhance the multibiological barrier penetrating capability for drug delivery in comparison with their soft and hard counterparts. [5] NPs with poly(ethylene glycol) (PEG) modification can effectively transport across various biological barriers. [6] The hydrophile-lipophile balance (HLB) is a key factor in the formation of self-assembled NPs and its morphology, [7] however, the role of HLB of NPs in drug delivery, particularly in penetration and retention in tumors, remains unclear.One of the challenges is to prepare NPs with a tunable ratio of hydrophilic to hydrophobic units, or a tunable HLB value, which governs the self-assembling behavior of the NPs. In our previous work, we have reported a linear-peptide dendritic copolymer and its conjugated hydrophobic drug (doxorubicin) could self-assemble into stable and tumor microenvironment-responsive NPs by nonbonding interactions, such as π-π stacking, hydrophobic interaction, and hydrogen bonding. [8] However, it is a challenge to obtain NPs from the linear dendritic copolymers with tunable HLB values.Herein, we employed 2,2-bis(hydroxymethyl)propionic acid (Bis-MPA) hyperbranched PEG-OH dendrimer as a hydrophilic unit and pyropheophorbide-a (Ppa) as a hydrophobic unit to Hydrophile-lipophile balance (HLB) has a great influence on the selfassembly and physicochemical properties of amphiphiles, thus affecting their biological effects. It is shown that amphiphilic nanoparticles (NPs) with a moderate HLB value display enhanced stability and highly efficient tumor retention. 2,2-Bis(hydroxymethyl)propionic acid hyperbranched poly(ethylene glycol) (PEG)-pyropheophorbide-a (Ppa) amphiphiles (G320P, G310P, G220P, and G210P) are synthesized with a tunable HLB value from 6.1 to 9.9 by manipulating the number of generation of dendrons (G2 or G3) and the molecular weight of PEG chains (10 or 20 kDa). Molecular dynamics simulations reveal that G320P and G210P with a moderate HLB value (8.0 and 7.8) self-assemble into very stable NPs with a small solvent accessible surface area and high nonbonding interactions. G320P with a moderate HLB value (8.0) and a long PEG chain excels against other NPs in prolonging the blood circulation time of Ppa (up to 13-fold), penetrating deeply into multicellular tumor spheroids and accumulating in tumors, and enhancing the PDT efficacy with a tumor growth inhibition of 96.0%. Rational design of NPs with a moderate HLB value may be implemented in these NP-derived nanomedicines to achieve high levels of retention in tumors. Hydrophile-Lipophile BalanceRational designs of nanomedicine aid in overcoming physiological barriers of solid tumors for achieving enhanced therapeutic efficacy, [1] including manipulating physical, chemical, and biological properties of nanoparticles. [2] Negatively charged nanoparticles (NPs) are very stable in the blood circulatory system, thereby allowing NPs accumulation in tumors through enha...

Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors

“…In recent years several studies have shown the ability of stimuli-responsive copolymer-drug bioconjugates to significantly improve the therapeutic index of the active compounds by means of increased accumulation in the tumor sites ( Chen et al, 2019b ; Zheng et al, 2019 ; Cai et al, 2020 ; Guo et al, 2020 ; Pan et al, 2020 ; Zhang et al, 2020 ). For example, Chen and coworkers developed two strategies to achieve this goal: a) through use of N-(1,3-dihydroxypropan-2-yl) methacrylamide with a high molecular weight (MW) linked to doxorubicin by an enzyme-responsive oligopeptide linker and b) by modifying the previously-decribed polymeric derivative by grafting PEG via a disulfide bond.…”

Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

“…A highly branched structure represented by dendritic polymers is the fourth form of polymeric architectures apart from linear, cross‐linked, and branched structures (Qu et al, 2019; Wei et al, 2016; Zheng et al, 2019). In view of structures and properties, this polymer can be divided into four major subclasses, as illustrated in Figure 1, including: (a) dendrons or dendrimers, (b) hyperbranched polymers or long chain hyperbranched polymers, (c) dendronized or dendrigraft polymers, and (d) dendritic hybrid polymers (i.e., branched‐linear block, branched core star, etc.…”

Recent advances on synthesis and biomaterials applications of hyperbranched polymers

“…The outer shell properties of hyperbranched polymers have also been utilized in a recent example, where thermal properties of guest‐loadable polymers have been used for protein purification by tuning the LCST to induce temperature‐selective complexation and precipitation of proteins (Carter et al, 2006). Numerous other examples of branched polymers were recently reported to exhibit self‐assembly and potential use as nanocarriers, including those synthesized by RAFT polymerization Ghosh Roy & De, 2014), NMP (Peleshanko, Gunawidjaja, Petrash, & Tsukruk, 2006), polyesterification (Zheng et al, 2019), Michael addition (Dong et al, 2019; Shang et al, 2019), and Friedel‐Crafts hydroxyalkylation reactions (Soultan et al, 2019). Regarding interesting microstructures, vesicle formation in solution has been studied for polymers based on hyperbranched dimethylpropanioc acid, which showed pH‐sensitive properties (Shi, Zhou, & Yan, 2008).…”