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<p>The use of monomethyl auristatin E (MMAE), a remarkably potent microtubule inhibitor, as a free medication is restricted due to its extreme systemic toxicity. While selectivity is improved by dedicated platforms like ADCs, issues with payload instability, burst release, and process scalability still exist. When paired with strong downstream purification, protein-polymer nanocomplexes present a viable way to separate cytotoxic efficacy from off-target damage. Using a double-emulsion solvent evaporation method and carbodiimide-mediated lactoferrin conjugation, a MMAE-loaded lactoferrin-PLGA nanocomplex has been developed. To purify and standardize the nanocomplex, tangential flow filtration (TFF, 300&#xa0;kDa MWCO) was optimized applying QbD principles. Physicochemical characteristics, cellular internalization (A549), in-vitro release, encapsulation efficiency, long-term stability (180 days), and in-silico ADMET–PBPK performance were all methodically assessed. TFF purification increased surface charge (− 21.5 mV vs. −10.2 mV) and decreased particle size from 252.8 ± 12.4&#xa0;nm (PDI 0.723) to 132.8 ± 6.3&#xa0;nm (PDI 0.121). While free drug content was selectively eliminated (~ 1.7-fold increase in permeate), encapsulation efficiency remained high (90.1 ± 1.4%) with &gt; 91% recovery yield. Purified nanocomplexes demonstrated good colloidal stability over 180 days with &lt; 1.3-fold size variation, enhanced cellular survival (~ 75% vs. ~ 40% for free MMAE, <i>p</i> &lt; 0.001), sustained, pH-responsive release up to 120&#xa0;h, and substantially decreased burst release. While significantly lowering nonspecific cytotoxicity, the TFF-optimized lactoferrin-PLGA nanocomplex represents a promising nanoformulation platform that could complement or inspire alternatives to current MMAE administration approaches, pending in vivo efficacy and safety evaluation.</p> Graphical Abstract <p></p>

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Tangential Flow Filtration-Optimized MMAE-Loaded Lactoferrin-PLGA Nanocomplex with Enhanced Stability, Controlled Release, and In-Silico ADMET Assessment

  • 期刊论文

  • 发表日期：

    2026年4月18日

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  • Nishabh Kushwaha,
  • Asha Patel,
  • Kshitija Akarte,
  • Shruti Patel,
  • Drishti Panjwani,
  • Mange Ram Yadav

摘要

The use of monomethyl auristatin E (MMAE), a remarkably potent microtubule inhibitor, as a free medication is restricted due to its extreme systemic toxicity. While selectivity is improved by dedicated platforms like ADCs, issues with payload instability, burst release, and process scalability still exist. When paired with strong downstream purification, protein-polymer nanocomplexes present a viable way to separate cytotoxic efficacy from off-target damage. Using a double-emulsion solvent evaporation method and carbodiimide-mediated lactoferrin conjugation, a MMAE-loaded lactoferrin-PLGA nanocomplex has been developed. To purify and standardize the nanocomplex, tangential flow filtration (TFF, 300 kDa MWCO) was optimized applying QbD principles. Physicochemical characteristics, cellular internalization (A549), in-vitro release, encapsulation efficiency, long-term stability (180 days), and in-silico ADMET–PBPK performance were all methodically assessed. TFF purification increased surface charge (− 21.5 mV vs. −10.2 mV) and decreased particle size from 252.8 ± 12.4 nm (PDI 0.723) to 132.8 ± 6.3 nm (PDI 0.121). While free drug content was selectively eliminated (~ 1.7-fold increase in permeate), encapsulation efficiency remained high (90.1 ± 1.4%) with > 91% recovery yield. Purified nanocomplexes demonstrated good colloidal stability over 180 days with < 1.3-fold size variation, enhanced cellular survival (~ 75% vs. ~ 40% for free MMAE, p < 0.001), sustained, pH-responsive release up to 120 h, and substantially decreased burst release. While significantly lowering nonspecific cytotoxicity, the TFF-optimized lactoferrin-PLGA nanocomplex represents a promising nanoformulation platform that could complement or inspire alternatives to current MMAE administration approaches, pending in vivo efficacy and safety evaluation.

Graphical Abstract