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Page 10 of 14 Kamal et al. J Cancer Metastasis Treat 2019;5:11 I http://dx.doi.org/10.20517/2394-4722.2018.89

Passive targeting could be a cheaper, long-term effective and safe technique to target tumor cells without
triggering resistance for active targeting moieties. Numerous significant downsides in active tumor-targeted
drug delivery were identified [115-120] . Interestingly, passive targeting can be tailored and designed via simple
ideologies and techniques such as simple PEGylation, size modifications or even shape customization. It
was shown that slender shape and particles modifications such as drifting from the conventional spherical
particulate structures, can yield high effectual passive targeting [121] .

Active targeting shows significant results in combating cancer initially with long-term degraded efficacy
profile, most potentially attributed to multidrug resistance [119] . Additionally, the marginally augmented
efficacy of active targeting strategies does not substantiate the extremely higher cost, difficulty in clinical
application and the high complexity level of the carrier system [54,78,115-120,122,123] . Interestingly, passive
targeting can be tailored and designed via simple ideologies and techniques such as simple PEGylation, size
modifications or even shape customization.

Multiple researchers suggested the preferential long-term advantage of passive targeting over active targeting
[123]
[122]
such as Lammers et al. and Rosenblum et al. . Such researches highlighted the need for future realistic
and scalable efforts to address some of the conceptual drawbacks of drug targeting to tumors such as
resistance, and that strategies should be developed to overcome these deficiencies. Such research presented
evidence that passive targeting yield very comparable results to active targeting on the short term and
superior results on the long term [54,78,115-120,122,123] .

Some of the main drawbacks of engineered nanotechnologies, either active or passive, are the poor robust
and cost-effective toolbox to characterize nanomaterials and to quantify exposure in test systems (dosimetry),
lack of standard techniques and methods for test, hazard, and risk assessment strategies and lack of specific
safety assessment strategies in evaluating nanotoxicities. However, passive targeting offers less problematic
strategy compared to active targeting engineered nanotechnologies in terms of nano-safety and its
quantitative characterization [124] .

Passive targeting could provide an applied direction for the advance of novel management tackles and
therapeutics for brain metastases of breast cancer for researchers worldwide, paving the road to affordable,
scalable, stable, efficient and safe management strategies. Such observations were evident from the multiple
passive targeting products under Phase II and Phase III clinical trials from multiple pharmaceutical firms
such as Nektar Therapeutics, BiOasis Inc. and 2-BBB. Such companies have invested heavily into the
development of new formulations that combat brain barriers, targeting the brain and accumulates in tumor
tissue rather than normal cells, to enhance the nano-safety profiles to chemotherapeutics. This may not
be only attributed to their need to expand their portfolio to increase their commercial value for possible
products buyouts and licensing by big pharmaceutical firms, but the safety and efficacy potential of such
passively targeted nanotherapeutics in the treatment strategies of brain metastases of breast cancer compared
to current conventional modalities and research-driven active-targeting initiatives.

Such conclusions have driven the industry to invest heavily on passive targeting compared to active
targeting. A major focus by industry is the successful transformation of such novel technologies from bench
to bedside with reasonable cost, scale-up abilities and formulation robustness and reproducibility, which
are achievable via passive targeting technologies compared to active targeting. Active targeting ligand
post-insertion and labeling techniques need to be extensively researched for ease of application for active
targeting to gain industrial momentum. Conclusively, patents and products under development should focus
on simple passively targeted bioconjugate structures, which are easily synthesized with high yield, reduced
cost and high stability profile of the final formulation.